EP4735452A2 - Heterobifunctional compounds for the degradation of kras protein - Google Patents

Abstract

The invention provides compounds that degrade the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein including mutant forms via the ubiquitination of the KRAS protein and subsequent proteasomal degradation. The compounds are useful for the treatment of various cancers.

Description

HETEROBIFUNCTIONAL COMPOUNDS FOR THE DEGRADATION OF KRAS PROTEIN CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63/524,516 filed June 30, 2023, which is incorporated by reference herein for all purposes. FIELD OF THE INVENTION The invention provides compounds that degrade a Kirsten rat sarcoma viral oncogene homolog (KRAS) protein, for example a mutant KRAS protein such as G12D-KRAS or gain- of-function KRAS mutations, for the treatment of abnormal cellular proliferation including cancers and tumors as described in more detail below. BACKGROUND OF THE INVENTION The rat sarcoma (RAS) family of viral oncogene homolog GTPases are involved in cellular signal transduction by acting as molecular switches to mediate cell growth, differentiation, and survival. The RAS family includes three distinct members, i.e. Harvey rat sarcoma viral oncogene homolog (HRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Neuroblastoma rat sarcoma viral oncogene homolog (NRAS). Upon GTP binding, the RAS GTPases engage effector proteins to initiate a variety of downstream signaling including the RAF-MEK-ERK and PI3K-AKT pathways that control mitogenic processes (Cox, A.D. & Der, C.J. Ras history: The saga continues. Small GTPases. 1(1):2-27(2010 Jul.)). Overexpression or mutation of these genes leads to the accumulation of GTP-bound KRAS and the unrestricted activation of RAF-MEK-ERK and PI3K-AKT signaling pathways and has been implicated in many types of human cancer including colorectal cancer, pancreatic cancer, lung cancer, and non-small cell lung cancer (NSCLC). Single amino acid substitutions caused by missense mutations are associated with 98% of RAS-related cancers and occur at mutational hotspots encoding codons including glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61) (Waters, A.M. & Der, C.J. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb. Perspect. Med. 8(9):a031435(2018 Sep)). Mutant KRAS accounts for approximately 84% of all RAS-mutant cancers (Id.). Gain-of-function KRAS mutations are found in approximately 30% of all human cancers (P. Liu et al., “Targeting the untargetable KRAS in cancer therapy”. Acta Pharm. Sinica B 2019; 9(5): 871–879; V. Merz et al., “Targeting KRAS: The Elephant in the Room of Epithelial Cancers”. Front. Oncol.2021, vol. 11, article 638360), including, e.g., pancreatic cancer (>80%), colon cancer (approximately 40-50%), lung cancer (approximately 30-50%), non-small cell lung cancer, myeloid leukemia breast cancer, cervical cancer, endometrial cancer, liver cancer, bladder cancer, and biliary tract malignancies (S. Jančík et al., “Clinical Relevance of KRAS in Human Cancers” J. Biomed. Biotechnol. 2010; 2010: 150960). Activating or gain- of-function mutations interfere with KRAS’s ability to flip between active and inactive states. Patients with KRAS mutations have historically exhibited poor responses to standard of care therapies. Despite the known role of KRAS as an oncogenic hub, the development of KRAS targeting agents has historically been extremely challenging, even earning the nickname, “the undruggable gene” (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol.15:152(2022)). In 2013, the lab of Kevan Shokat at the University of California San Francisco identified an allosteric pocket, termed the switch-II pocket, on KRAS which could by bound by inhibitors (Ostrem, J. et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 503(7477): 548-551). Although this allosteric site is adjacent to the nucleotide binding pocket, it is transiently formed and was not observed in previous crystal structures of the protein. A compound binding in the switch-II pocket alters the relative binding affinity of KRAS to GTP and GDP, favoring the inactive GDP-bound form. Three years later, the first low micromolar compounds against KRAS G12C were disclosed by Wellspring Biosciences (Patricelli, M. et al. Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Cancer Discovery 6(3):316-29, 2016). In 2018, Wellspring Biosciences published a paper describing improved KRAS binders with a 4- piperazinyl-quinazolinyl-7-phenol pharmacophore (Janes, M. et al. Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor, Cell, 172, 578-589). Only recently have KRAS targeting agents been developed and approved by the United States Food and Drug Administration (FDA), albeit for a specific subset of KRAS mutant patients (Huang, L. et al. KRAS mutation: from undruggable to druggable in cancer. Sig Transduct Target Ther. 6(1):386(2021 Nov 15)). Sotorasib (Lumakras®) and adagrasib (Krazati®), indicated for locally advanced or metastatic non-small cell lung cancer are irreversible inhibitors of KRAS G12C that covalently bind the mutant cysteine of KRAS, locking the protein into an inactive state, thereby preventing downstream signaling without affecting the wild-type protein (Lumakras® Package Insert (2022 Dec); Krazati® Package Insert (2021 May)). While novel KRAS G12C inhibitors have achieved beneficial results, acquired treatment resistance is expected to rapidly develop in this patient population, potentially due to a complex combination of multiple mechanisms. Some potential mechanisms of resistance include release of ERK-mediated feedback inhibition, development of secondary KRAS mutations, re- activation of KRAS through activation of receptor tyrosine kinases (RTKs), PI3K activation by the IGFR–IRS1 pathway, and simultaneously converging resistance mechanisms (Id.). The field of targeted protein degradation promoted by small molecules has been intensively studied (Collins, I. et al. Chemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway. Biochem J.474(7):1127-1147(2017 Mar 15)). Protein degradation plays a role in various cellular functions. For example, the body uses protein degradation to adjust the concentrations of regulatory proteins through degradation into small peptides to maintain health and productivity of the cells. Cereblon is a protein that forms an E3 ubiquitin ligase complex, which ubiquitinates various other proteins. Cereblon is known as the primary target for the anticancer thalidomide analogs. A higher expression of cereblon has been linked to the efficiency of thalidomide analogs in cancer therapy. Modulators for targeted ubiquitination include those described by Arvinas in WO2015160845, WO2016149668, WO2016197032, WO2017011590, WO2017030814, WO2018144649, WO2018226542, and WO2019199816; those described by Dana-Farber Cancer Institute in WO2016105518, WO2017007612, WO2017024317, WO2017024318, WO2017117473, WO2017117474, WO2018148443, WO2018148440, and WO2019165229; those described by Kymera in WO2019/060742, WO2019/140387, and WO2020/01022; and those described by C4 Therapeutics Inc. in WO2017197036, WO2017197046, WO2017197051, WO2017197055, WO2018237026, WO2019099868, WO2019191112, WO2019204353, WO2019236483, WO2020132561, WO2020181232, WO2020210630, WO2021127561, WO2021178920, WO2021255212, WO2021255213, WO2022032026, WO2022032132, WO2022081925, WO2022081928, WO2022235945, WO2022251539, WO2022261250, WO2022251539, WO2023283372, WO2023039208, WO2023055952, WO2023239750, and WO2023244764. Some specific molecules for the degradation of KRAS have also been described (Cheng, J. et al. Discovery of Novel PDEδ Degraders for the Treatment of KRAS Mutant Colorectal Cancer. J Med Chem. 63(14):7892-7905(2020 Jul 23); Zeng, M. et al. Exploring Targeted Degradation Strategy for Oncogenic KRAS^G12C. Cell Chem Biol.27(1):19-31.e6(2020 Jan 16); Bond, M.J. et al. T d d i f i b L-Recruiting PROTACs. ACS Cent Sci. 6(8):1367-1375(2020 Aug 26)). Additional examples of KRAS degraders are described in Fell, J.B. et al. Identification of the Clinical Development Candidate MRTX849, a Covalent KRAS^G12C Inhibitor for the Treatment of Cancer, J. Med. Chem. 202063 (13), 6679- 6693; Fell, J.B. et al., Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS G12C with In Vivo Activity, ACS Med. Chem. Lett.2018, 9, 12, 1230–1234; Wang, X. et al. “Identification of MRTX1133, a Noncovalent, Potent and Selective KRAS^G12D Inhibitor, J. Med. Chem. 2022, 65, 4, 3123–3133; Canon, J. et al., The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumor immunity, Nature, 2019 Nov;575(7781):217-223; Zhang et al. Chemoselective covalent modification of K-Ras(G12R) with a Small Molecule Electrophile, J. Am. Chem. Soc. 2022, 144, 35, 15916-15921. Patent applications describing KRAS degraders include WO2024119278, WO2024118966, WO2024118960, WO2024055112, WO2024019103, WO2024001839, WO2024054625, WO2024050742, WO2023193085, WO2023205719, WO2023205701, WO2023215802, WO2023215906, WO2023116934, WO2023215801, WO2023280026, WO2023185864, WO2023141570, WO2023138524, WO2022266206, WO2022228576, WO2019195609, CN115785199, CN115260158, CN116332959, and CN116375742. There remains a need for new KRAS modulators to treat disorders mediated by KRAS, for example mutant KRAS, in a host in need thereof. Therefore, it is an object of the present invention to provide new compounds, pharmaceutical compositions, methods of use and manufacture, to treat disorders mediated by KRAS in a host such as a human. SUMMARY OF THE INVENTION Compounds and their uses and manufacture are provided that degrade the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein via the ubiquitin proteasome pathway (UPP). These compounds include a Targeting Ligand that binds to KRAS, an E3 Ligase binding portion (Heterocyclic Moiety^A or Heterocyclic Moiety^B), and a Linker that covalently links the Targeting Ligand to the E3 Ligase binding portion. In certain embodiments a compound of the present invention degrades KRAS with a mutation or combination of mutations, for example a G12D mutation or a mutation selected from G12A, G12C, G12D, G12R, G12V, and G13D, or a combination thereof. In certain embodiments a compound of the present invention is a selective degrader of G12D containing KRAS mutants. In certain aspects the present invention provides a compound of Formula IA or Formula IB: or a pharmaceutically acceptable salt thereof; wherein: KRAS Targeting Ligand^B is ; Heterocyclic Moiety^A is selected from: , Heterocyclic Moiety^B is selected from: or Heterocyclic Moiety^B is selected from:

R¹ and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R¹ and R⁶ are combined to form a one or two carbon bridge to form a fused cycle, for each R² and R⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R⁹, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)2R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)2R⁹, -SC(O)R⁹, -OS(O)2R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, - NR⁷P(O)(R⁹)2, and -OP(O)(R⁹)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R¹⁶ is selected from: , , , , and , and R¹², each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R^16B is selected from: , , , and ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; -8- R¹⁷ is selected from: , and , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R^17B is selected from: R¹⁸ is a 9-membered heteroaryl attached to the azaglutarimide moiety through a C-N bond, optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; for Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; Cycle² is a fused heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; R¹² is the attachment point to Linker; R⁷ and R⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR⁷R⁸, -OR⁷, and -SR⁷ each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; R¹¹ and R¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2; Linker is a bivalent chemical group;

KRAS Targeting Ligand^A is selected from: R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; R³⁰ and R³¹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R³² is selected from: and ; wherein attachment point is attached to the Linker and the remaining attachment point is attached to the KRAS Targeting Moiety; for example when the formula includes a compound of Formula ; the embodiments below do not include , but the attachment point to Linker is clear from context and the R³² formula from which they depend; In certain embodiments, R³² is selected from:

In certain embodiments, R³² is selected from: R⁵¹ and R^51A are independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; In certain embodiments, two R⁵¹ groups, together with the atoms to which they are attached form a ring. When the two R⁵¹ groups are on the same atom, the formed ring would be a spirocyclic ring. For example, an R³² group of the formula includes compounds such as . When the two R⁵¹ groups are on different atoms, the formed ring would be a fused or bridging ring. For example, an R³² group of the formula includes compounds such a group of the formula includes compounds such R^51B is independently selected from halogen, cyano, haloalkyl, -OR⁷, and -SR⁷; R^51C is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD3; R^51D and R^51E are independently hydrogen, alkyl, alkenyl, haloalkyl, cyano, -OR⁷, and - SR⁷or together with X^B and the carbon atoms to which they are attached, form a 5-, 6-, or 7- membered ring; R⁸⁸ is selected at each instance from aryl, heteroaryl, heterocycle, bicycle, and spirocycle; z is independently selected at each instance from 0, 1, 2, 3, or 4 as allowed by valence; q is 1, 2, 3, or 4; w is 1, 2, 3, or 4; X^A is selected from -CH- and -N-; X^B is selected from -CH2-, -C(R⁵¹)2-, -O-, -NH-, -N(R⁴)-, and -S-; R³³ is selected from: each of which R³³ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; R³⁸ and R³⁹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, and heterocycle each of which except hydrogen and halogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; in certain embodiments, an R³³ group of the formula is selected from:

R⁵² and R⁵⁴ are independently selected at each instance from hydrogen, halogen, cyano, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R⁵³ and R⁵⁵ are independently selected at each instance from hydrogen, halogen, cyano, alkyl, haloalkyl, -NR⁷R⁸, -OR⁷, -SR⁷, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle; R⁵⁷ is independently selected from hydrogen, alkyl, haloalkyl, arylalkyl, C(O)R⁴, C(O)NR⁷R⁸, and R⁷; R⁴¹, R⁴², R⁴³, and R⁴⁴ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; and each R⁴⁵, R⁴⁶, and R⁴⁷ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵. In certain embodiments Linker is selected from wherein: X¹ and X² are independently at each occurrence selected from bond, heterocycle, NR², C(R²)2, O, C(O), and S; R²⁰, R²¹, R²², R²³, and R²⁴ are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO₂-, -S(O)-, -C(S)-, -C(O)NR²-, -NR²C(O)-, -O-, -S-, -NR²-, -C(R⁴⁰R⁴⁰)-, -P(O)(OR²⁶)O-, -P(O)(OR²⁶)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁰; R²⁶ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; and R⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, - NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), - N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, - NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl. Another aspect the present invention provides a compound of Formula XA or XB: or a pharmaceutically acceptable salt thereof; wherein LinkerB is selected from: X²² is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)₂R⁹, -SC(O)R⁹, -OS(O)₂R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)2R⁹, -P(O)(R⁹)2, -SP(O)(R⁹)2, - NR⁷P(O)(R⁹)₂, and -OP(O)(R⁹)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; and all other variables are defined herein. Every combination of variables, substituents, embodiments and the compounds that result from these combinations, is deemed specifically and individually disclosed, as such depiction is for convenience of space only and not intended to describe only a genus or even a subgenus of compounds. A compound of the present invention provided herein or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable composition can be used to treat a disorder which is mediated by KRAS. In some embodiments a method to treat a patient with a disorder mediated by KRAS is provided that includes administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to the patient, typically a human, optionally in a pharmaceutically acceptable composition. A compound of the present invention may be used to treat a KRAS-mediated disorder such as colon cancer; rectal cancer; endometrial cancer; lung cancer, including non-small cell lung cancer; pancreatic cancer; thyroid cancer; astrocytoma; esophageal cancer; cervical cancer; small intestinal cancer; ovarian cancer; gastric cancer; breast cancer; bladder cancer; or kidney cancer. In certain embodiments, a method of treatment is provided comprising administering an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof to a human patient in need thereof, optionally in a pharmaceutically acceptable carrier. For example, in certain embodiments, a compound of the present invention is administered to a human to treat a cancer. In certain embodiments a compound of the present invention is used to treat lung cancer. In certain embodiments, the lung cancer is non-small cell lung cancer. In certain embodiments a compound of the present invention is used to treat colorectal or rectal cancer. In certain embodiments a compound of the present invention is used to treat pancreatic cancer. In certain embodiments a compound of the present invention is used to treat pancreatic ductal adenocarcinoma (PDAC). In certain embodiments, the compound of the present invention provides one or more, and even may provide multiple advantages over traditional treatment with a KRAS inhibitor. For example, the KRAS degrading compound of the present invention may a) overcome resistance in certain cases; b) prolong the kinetics of drug effect by destroying the protein, thus requiring resynthesis of the protein even after the compound has been metabolized; c) target all functions of a protein at onc h h ifi l i i i bi ding event; and/or d) have increased potency compared to inhibitors due to the possibility of the small molecule acting catalytically. In one aspect, a compound of the present invention is used to treat a KRAS mediated cancer, wherein the KRAS has mutated from the wild-type. There are a number of possibilities for KRAS mutations. In certain non-limiting embodiments, the mutation encodes a missense substitution at a codon selected from glycine-12 (G12), glycine-13 (G13), glutamine 61 (Q61), or any combination thereof. In certain nonlimiting embodiments, the mutation encodes a missense substitution selected from K5E, K5N, G12A, G12C, G12D, G12E, G12F, G12I, G12L, G12N, G12R, G12S, G12V, G12W, G12Y, G13A, G13C, G13D, G13E, G13I, G13N, G13R, G13S, G13V, V14I, P34L, P34Q, P34R, I36M, T58I, A59S, A59T, G60R, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, R68S, H95D, H95Q, H95R, Y96C, Y96D, V152G, D153V, F156I, F156L, or a combination thereof. In certain aspects the mutation is G12D. In certain aspects, the cancer has developed one or more KRAS mutations following treatment with at least one KRAS inhibitor including but not limited to covalent inhibitors sotorasib (Lumakras®) and adagrasib (Krazati®). In yet another aspect, the cancer has one or more KRAS missense mutations encoding codon substitutions or optionally non-KRAS mutations that renders the cancer intrinsically resistant to KRAS inhibitor treatment, for example, KRAS with a G12D mutation. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired a resistance to, a KRAS inhibitor such as Sotorasib (AMG- 510; Lumakras®), adagrasib (MRTX849; Krazati®), 12VC1, ARS-1620, ARS-3248, ARS-853, AZD4785, Bi-2852, BI 1823911, D-1553, GDC-6036, JAB-21822, JDQ443, JNJ-74699157, KRpep-2d, KS-58, LY3537982, MK-1084, MRTX1133, or SML-8-73-1. In certain embodiments the compound of the present invention is used to treat a mutant KRAS mediated disorder, wherein KRAS has a substitution of at least one of the below listed amino acid sites, or a combination thereof. The substitution may, for example, be G12D and one or more additional mutations selected from the listed exemplary substitutions, or may be a different substitution. Table 1. Exemplary KRAS Substitutions. ¹ Specific substitution frequencies at codons G12, G13, and Q61 calculated according to COSMIC database (Cox, A.D. & Der, C.J. Ras history: The saga continues. Small GTPases. 1(1):2-27(2010 Jul)). In certain embodiments the mutant KRAS mediated disorder has two substitutions selected from the table above. In other embodiments the mutant KRAS mediated disorder has three substitutions selected from the table above. In other embodiments the mutant KRAS mediated disorder has four or more substitutions selected from the table above. In certain embodiments the mutant KRAS mediated disorder has an G12D substitution and one additional substitution which may optionally be selected from the table above. In some of these embodiments the mutant KRAS mediated disorder has an G12D mutation and two additional substitutions that may optionally be selected from the table above. In other embodiments the mutant KRAS mediated disorder has a G12D mutation and three additional substitutions selected from the table above. In certain embodiments, the mutant KRAS mediated disorder has any one of the substitutions listed in Table 1 above and one or more additional non-KRAS mutations. In some embodiments, the non-KRAS mutation is selected from a mutation in TP53, STK1, EGFR, or a combination thereof. In certain embodiments the KRAS mediated disorder is mutant KRAS mediated cancer. In certain embodiments a compound of the present invention is used to treat G12D mutant KRAS cancer. In certain embodiments, a compound of the present invention is used to treat G12V mutant KRAS cancer. In certain embodiments, the compound of the present invention provides an improved efficacy and/or safety profile relative to at least one known KRAS inhibitor. For example, the degrader of the present invention has the efficiency of an inhibitor only protein binding moiety combined with the catalytic degradation activity of the cereblon-activiated protesomal degradation. This provides rapid activity against the target overexpressed KRAS by an active moiety that can quickly “return to action” and repeat the catalytic function. In this way, the KRAS is quickly destroyed, in contrast to a covalent inhibitor, like sotorasib (Lumakras®). In certain embodiments, the degrader compound of the present invention has one or more advantages in the treatment of KRAS mediated disorders compared to using an enzyme inhibitor only. In certain embodiments, less of the compounds described herein are needed for the treatment of a KRAS mediated disorder, than by mole of the KRAS Targeting Ligand portion alone. In certain embodiments, KRAS Targeting Ligand is KRAS Targeting Ligand^A. In certain embodiments, KRAS Targeting Ligand is KRAS Targeting Ligand^B. In certain embodiments, the compound of the present invention has less of at least one side-effect in the treatment of a KRAS mediated disorder, than by mole of the KRAS Targeting Ligand portion alone. In certain embodiments, a less frequent dose regimen of a selected compound described herein is needed for the treatment of a KRAS mediated disorder, than the dose by mole of the KRAS Targeting Ligand portion alone. Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for treating a disorder mediated by KRAS or for modulating or decreasing the amount of KRAS. Another aspect of the present invention provides a compound as described herein, or an enantiomer, diaste i h f h i ll acceptable salt, hydrate, or solvate thereof, or its pharmaceutical composition, for use in the manufacture of a medicament for treating a disease mediated by KRAS. In certain embodiments, a selected compound as described herein is useful to treat a disorder comprising an abnormal cellular proliferation, such as a tumor or cancer, wherein KRAS is an oncogenic protein or a signaling mediator of the abnormal cellular proliferative pathway and its degradation decreases abnormal cell growth. In certain embodiments, the selected compound of the present invention or its pharmaceutically acceptable salt thereof, has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. In certain embodiments, the compound of the present invention or its pharmaceutically acceptable salt thereof, includes a deuterium atom or multiple deuterium atoms. Other features and advantages of the present application will be apparent from the following detailed description. The present invention thus includes at least the following features: (a) A compound of Formula IA or Formula IB, as described herein, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof; (b) A method for treating a KRAS mediated disorder, such as an abnormal cellular proliferation, including cancer, comprising administering an effective amount of a compound of Formula IA or Formula IB, or pharmaceutically acceptable salt thereof, as described herein, to a patient in need thereof; (c) A compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt, or isotopic derivative (including a deuterated derivative) thereof for use in the treatment of a disorder that is mediated by KRAS, for example an abnormal cellular proliferation such as a tumor or cancer; (d) Use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in an effective amount in the treatment of a patient in need thereof, typically a human, with a KRAS mediated disorder, for example an abnormal cellular proliferation such as a tumor or cancer; (e) Use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof in the manufacture of a medicament for the treatment of a KRAS mediated disorder, for example an abnormal cellular proliferation such as a tumor or cancer; (f) A method for treating a mutant KRAS mediated disorder, such as an abnormal cellular proliferation, including cancer, comprising administering an effective amount of a compound of Formula IA or Formula IB, or pharmaceutically acceptable salt thereof, as described herein, to a patient in need thereof; (g) A compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt, or isotopic derivative (including a deuterated derivative) thereof for use in the treatment of a disorder that is mediated by mutant KRAS, for example an abnormal cellular proliferation such as a tumor or cancer; (h) Use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, in an effective amount in the treatment of a patient in need thereof, typically a human, with a mutant KRAS mediated disorder, for example an abnormal cellular proliferation such as a tumor or cancer; (i) Use of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof in the manufacture of a medicament for the treatment of a mutant KRAS mediated disorder, for example an abnormal cellular proliferation such as a tumor or cancer; (j) A pharmaceutical composition comprising an effective patient-treating amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt, isotopic derivative thereof; and optionally a pharmaceutically acceptable carrier or diluent; (k) A compound Formula I, as described herein as a mixture of enantiomers or diastereomers (as relevant), including as a racemate; (l) A compound of Formula IA or Formula IB, as described herein in enantiomerically or diastereomerically (as relevant) enriched form, including an isolated enantiomer or diastereomer (i.e., about greater than 85, 90, 95, 97, or 99% pure); (m) A process for the preparation of therapeutic products that contain an effective amount of a compound of Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, as described herein; and (n) A compound of Formula XA or Formula XB, as described herein, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof. DETAILED DESCRIPTION OF THE INVENTION Compounds and their uses and manufacture are provided that degrade the Kirsten rat sarcoma viral onco h l ( ) i i h bi ii teasome pathway (UPP). These compounds include a Targeting Ligand that binds to KRAS, an E3 Ligase binding portion (Heterocyclic Moiety^A or Heterocyclic Moiety^B), and a Linker that covalently links the Targeting Ligand to the E3 Ligase binding portion. In certain embodiments a compound of the present invention degrades KRAS with a mutation or combination of mutations, for example a G12D mutation or a mutation selected from G12A, G12C, G12D, G12R, G12V, and G13D, or a combination thereof. In certain embodiments a compound of the present invention is a selective degrader of G12D or G12V containing KRAS mutants. In certain embodiments a compound of the present invention degrades wild-type KRAS. I. DEFINITIONS Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. The compounds of the present invention may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, isomer; such as rotamer, as if each is specifically described unless specifically excluded by context. The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item(s). The term “or” means “and/or”. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. The present invention includes a compound of the present invention with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, and ¹²⁵I respectively. In certain embodiments, isot i ll l b ll d d b d i abolic studies (with, for example ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In certain embodiments, deuterium is 90, 95 or 99% enriched at a desired location. In certain embodiments, the substitution of a hydrogen atom for a deuterium atom can be provided in any compound of the present invention. In certain embodiments, the substitution of a hydrogen atom for a deuterium atom occurs within one or more groups selected from any of R’s or variables described herein, Linker, and KRAS Targeting Ligand^A or KRAS Targeting Ligand^B. For example, when any of the groups are, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting embodiments, CDH₂, CD₂H, CD_3, CH₂CD₃, CD₂CD₃, CHDCH₂D, CH₂CD₃, CHDCHD₂, OCDH₂, OCD₂H, or OCD3 etc.). In certain other embodiments, when two substituents are combined to form a cycle, the unsubstituted carbons may be deuterated. In certain embodiments, a compound of the present invention is isotopically labeled. In certain embodiments, at least one R group is isotopically labeled with 1, 2, or more isotopes as allowed by valence. In certain embodiments, the isotopic label is deuterium. In certain embodiments, at least one deuterium is placed on an atom that has a bond which is broken during metabolism of the compound in vivo, or is one, two or three atoms remote form the metabolized bond (e.g., which may be referred to as an α, β or γ, or primary, secondary or tertiary isotope effect). In other embodiments, the isotopic label is ¹³C. In other embodiments, the isotopic label is ¹⁸F. The compound of the present invention may form a solvate with a solvent (including water). Therefore, in certain non-limiting embodiments, the invention includes a solvated form of the compound. The term “solvate” refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are w h l i l di h l lf id tone and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a compound of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g., D2O, acetone-d6, DMSO- d₆ (dimethyl sulfoxide). A solvate can be in a liquid or solid form. A dash ( “ ”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH₂ is attached through carbon of the carbonyl (C=O) group. “Alkyl” is a branched or straight chain saturated aliphatic hydrocarbon group. Unless denoted otherwise, “alkyl” is typically a C1-C8 alkyl. In certain non-limiting embodiments, the alkyl group contains from 1 to 12 carbon atoms, more generally from 1 to 6 carbon atoms or from 1 to 4 carbon atoms. In certain non-limiting embodiments, the alkyl contains from 1 to 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species. For example, the term C1-C6 alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and therefore each subset is considered separately disclosed. For example, the term C₁-C₄ alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2- dimethylbutane, and 2,3-dimethylbutane. The term “alkyl” also encompasses cycloalkyl or carbocyclic groups. For example, when a term is used that includes “alk” then “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example, and without limitation, the terms alkyl, alkoxy, haloalkyl, etc., can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context. Non-limiting examples of “cycloalkyl” include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the cycloalkyl ring. The term “alkoxy” denotes a group of the formula -O-alkyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. The term “cycloalkoxy” denotes a group of the formula -O-cycloalkyl. Examples of cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy. “Alkenyl” is a linear or branched aliphatic hydrocarbon groups having one or more carbon-carbon double bonds that may occur at a stable point along the chain. Unless denoted otherwise, “alkenyl” is typically a C₂-C₈ alkenyl. The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. In certain non-limiting embodiments, the alkenyl contains from 2 to 12 carbon atoms, from 2 to 6 carbon atoms or from 2 to 4 carbon atoms. In certain embodiments, the alkenyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6alkenyl. Examples of alkenyl radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4- methylbutenyl. The term “alkenyl” also embodies “cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z” alkenyl geometry. The term “Alkenyl” also encompasses cycloalkyl or cycloalkyl groups possessing at least one point of unsaturation. “Alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain. Unless denoted otherwise, “alkynyl” is typically a C₂-C₈ alkynyl. The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. In certain non-limiting embodiments, the alkynyl contains from 2 to 12 carbon atoms, more generally from 2 to 6 carbon atoms or from 2 to 4 carbon atoms. In certain embodiments, the alkynyl is C₂, C₂-C₃, C₂-C₄, C₂-C₅, or C₂-C₆alkynyl. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3- butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl and 5-hexynyl. The term “Alkynyl” also encompasses cycloalkyl or cycloalkyl groups possessing at least one triple bond. “Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example, can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6-carbon moiety, or an indicated number of carbon atoms, for example C₁-C₂alkylene, C₁-C₃alkylene, C₁-C₄alkylene, C₁-C₅alkylene, or C₁-C₆alkylene. “Alkenylene” is a bivalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6-carbon moiety, or an indicated number of carbon atoms, for example C2-C4alkenylene. “Alkynylene” is a bivalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylenes, for example, can be a 2 to 8 carbon moiety, a 2 to 6-carbon moiety, or an indicated number of carbon atoms, for example C2-C4alkynylene. The term “cyano” denotes a -C≡N group. The term “hydroxy” denotes a -OH group. “Halo” and “Halogen” refers independently to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Unless otherwise indicated “halo” or “halogen” typically refers to fluorine (F), chlorine (Cl), and bromine (Br). In certain embodiments “halo” or “halogen” is fluorine (F). “Haloalkyl” is a branched or straight-chain alkyl groups substituted with 1 or more halo atoms described above, up to the maximum allowable number of halogen atoms. Unless denoted otherwise, “haloalkyl” is typically a C1-C4 haloalkyl. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Perhaloalkyl” means an alkyl group having all hydrogen atoms replaced with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl. “Chain” indicates a linear chain to which all other chains, long or short or both, may be regarded as being pendant. Where two or more chains could equally be considered to be the main chain, “chain” refers to the one which leads to the simplest representation of the molecule. “Haloalkoxy” indicates a haloalkyl group as described herein attached through an oxygen bridge (oxygen of an alcohol radical). “Heterocycloalkyl” is an alkyl group as described herein substituted with a heterocyclo group as described herein. “Arylalkyl” is an alkyl group as described herein substituted with an aryl group as described herein. Non-limiting examples of “arylalkyl” include: , , , , , or . In certain embodiments, “arylalkyl” is . In certain embodiments, the “arylalkyl” refers to a 2-carbon alkyl group substituted with an aryl group. Non-limiting examples of “arylalkyl” also include: . In certain embodiments, the “arylalkyl” refers to a 3-carbon alkyl group substituted with an aryl group. “Heteroarylalkyl” is an alkyl group as described herein substituted with a heteroaryl group as described herein. As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6– 14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocycle groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. The one or more fused carbocyclyl or heterocycle groups can be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocycle groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4-methylenedioxyphenyl group. In certain embodiments, “aryl” is a 6-carbon aromatic group fused to a heterocycle wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring. In certain embodiments, “aryl” is a 6-carbon aromatic group fused to a cycloalkyl wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the aromatic ring. The term “heterocyclyl”, “heterocycle”, and “heterocyclo” includes saturated, and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. This term should not be confused with the capitalized terms “Heterocyclic Moiety^A” and “Heterocyclic Moiety^B” that are in the present invention and separately defined. Heterocyclic rings comprise monocyclic 3, 4, 5, 6, 7, 8, 9, or 10 membered rings, as well as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems). It does not include rings containing -O-O-, -O-S- or -S-S- portions. Examples of saturated heterocyclo groups include saturated 3, 4, 5, or 6-membered heteromonocyclic groups containing 1, 2, 3, or 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3, 4, 5, or 6- membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms [e.g., morpholinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclo groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3- dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4- triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3- dihydro-1H-1λ’-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, isoquinolin-1(2H)-onyl, benzo[d]oxazol-2(3H)-onyl, 1,3-dihydro-2H-benzo[d]midazol-2-onyl, benzo[d]thiazole-2(3H)- onyl, 1,2-dihydro-3H-pyrazol-3-onyl, 2(1H)-pyridinonyl, 2-piperazinonyl, indolinyl, and dihydrothiazolyl. The term “heterocyclyl”, “heterocycle”, and “heterocyclo” groups also include moieties where heterocycle radicals are fused/condensed with aryl or heteroaryl radicals: such as unsaturated condensed heterocycle group containing 1, 2, 3, 4, or 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocycle group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms, unsaturated condensed heterocycle group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocycle group containing 1 or 2 oxygen or sulfur atoms. Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocycle ring. For example, group. However, group. The term “heteroaryl” denotes a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) and 1, 2, 3, 4, 5, or 6, heteroatoms independently selected from O, N, and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized. Examples include, but are not limited to, unsaturated 5- to 6-membered heteromonocyclyl groups containing 1, 2, 3, or 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H- 1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- or 6- membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- oxadiazolyl]; unsaturated 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. Additional examples include 8 9 or 10 membered heteroaryl bicyclic groups such as indazolyl, indolyl, imidazo[1,5-a]pyridinyl, benzimidazolyl, 4(3H)-quinazolinonyl, quinolinyl, isoquinolinyl, isoindolyl, thienothienyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzoxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnolinyl, and triazolopyridinyl. The term “bicycle” refers to a ring system wherein two rings are fused together and each ring is independently selected from carbocycle, heterocycle, aryl, and heteroaryl. Bicyclic ring systems also include spiro-fused bicyclic ring systems. Non-limiting examples of bicycle groups include: , When the term “bicycle” is used in the context of a bivalent residue such as Linker the attachment points can be on separate rings or on the same ring. In certain embodiments, both attachment points are on the same ring. In certain embodiments, both attachment points are on different rings. Non-limiting examples of bivalent bicycle groups include: , “Aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon that is not aromatic. “Aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions. In certain embodiments, “aliphatic” is used to indicate those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in a cis- or trans-configuration. In certain embodiments, the aliphatic group contains from 1 to 12 carbon atoms, more generally from 1 to 6 carbon atoms or from 1 to 4 carbon atoms. In certain embodiments, the aliphatic group contains from 1 to 8 carbon atoms. In certain embodiments, the aliphatic group is C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅ or C₁-C₆. The specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species. For example, the term C₁-C₆ aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C₁-C₄ aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. The term “heteroaliphatic” refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom. In certain embodiments, the only heteroatom is nitrogen. In certain embodiments, the only heteroatom is oxygen. In certain embodiments, the only heteroatom is sulfur. “Heteroaliphatic” is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In certain embodiments, “heteroaliphatic” is used to indicate a heteroaliphatic group (cyclic, acyclic, branched or unbranched) having 1-20 carbon atoms. Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, and alkyl-O-haloalkyl. A “dosage form” means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like. A “dosage form” can also include an implant, for example an optical implant. An “effective amount” as used herein, means an amount which provides a therapeutic benefit. “Parenteral” administration of a pharmaceutical composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), intrasternal injection, or infusion techniques. Throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and should not be construed as a limitation on the scope of the invention. The description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. As used herein, “pharmaceutical compositions” are compositions comprising at least one active agent, and at least one excipient. The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use. As used herein, “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, non- toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH₂)_n-COOH where n is 0-4, and the like, or using a different acid that produces the same counterion. Lists of additional suitable salts may be found, e.g., in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p.1418 (1985). The term “pharmaceutically acceptable auxiliary substance” refers to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation. A “patient” or “subject” is a human or non-human animal in need of treatment of any of the disorders as specifically described herein, for example that is modulated by a natural (wild- type) or modified (non-wild type) protein that can be degraded according to the present invention, resulting in a therapeutic effect. As described further herein, the word patient or subject typically refers to a human patient or subject unless it is clear from the context or wording that the disclosure is meant to include a non-human animal. Typically, the patient is a human. In other embodiments, the patient or subject is a non-human animal in need of such therapy and responsive thereto. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In the specification, singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed application. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. II. COMPOUNDS OF THE PRESENT INVENTION In certain embodiments the compound of the present invention is selected from

or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from

or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from

or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from

Linker R⁴⁷ R³² R⁴⁶ R³⁰ N HN N N N N R³³ N ^O O ^O _H R⁴⁵ or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from O NH R⁴⁷ R³² Linker N O R⁴⁶ N N N O N R³³ R³⁰ R⁴⁵ Linker R⁴⁷ R³² R⁴⁶ N N N N ^O N R^{33 O} _H R³⁰ R⁴⁵

or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from

or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from

or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from:

; or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from:

, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of the present invention is selected from or a pharmaceutica ADDITIONAL EMBODIMENTS A1.A compound of Formula: or a pharmaceutically acceptable salt thereof; wherein: Heterocyclic Moiety^A is selected from: , R¹ and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R¹ and R⁶ are combined to form a one or two carbon bridge to form a fused cycle, for each R² and R⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R⁹, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)2R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)2R⁹, -SC(O)R⁹, -OS(O)2R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, - NR⁷P(O)(R⁹)2, and -OP(O)(R⁹)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R¹⁶ is selected from: substituents independently selected from R⁵; R¹⁷ is selected from: , , , , , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R¹⁸ is a 9-membered heteroaryl attached to the azaglutarimide moiety through a C-N bond, optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; for Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; R¹² is the attachment point to Linker; R⁷ and R⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR⁷R⁸, -OR⁷, and -SR⁷ each of which is optionally substituted with 1, 2, 3, or 4 substitue i d d l l d f R¹⁰ each R¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; R¹¹ and R¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2; Linker is of Formula: ; X¹ and X² are independently at each occurrence selected from bond, heterocycle, NR², C(R²)2, O, C(O), and S; R²⁰, R²¹, R²², R²³, and R²⁴ are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR²-, -NR²C(O)-, -O-, -S-, -NR²-, -C(R⁴⁰R⁴⁰)-, -P(O)(OR²⁶)O-, -P(O)(OR²⁶)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁰; R²⁶ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; R⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl)₂, -NHSO₂(alkyl), -N(alkyl)SO₂alkyl, -NHSO₂(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO₂alkenyl, -NHSO₂alkynyl, -N(alkyl)SO₂alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl; KRAS Targeting Ligand^A is selected from: , , , R⁴¹ R⁴² R³² R⁴³ N R⁴⁴ R²⁹ N R³³ R³⁸ R³⁹ , , , , , and ; R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; R³⁰ and R³¹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R³² is selected from: and ; wherein attachment point is attached to the Linker and the remaining attachment point is attached to the KRAS Targeting Moiety; R⁵¹ is selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; or two R⁵¹ groups, together with the atoms to which they are attached form a ring; R⁸⁸ is selected at each instance from aryl, heteroaryl, heterocycle, bicycle, and spirocycle; z is independently selected at each instance from 0, 1, 2, 3, or 4 as allowed by valence; q is 1, 2, 3, or 4; w is 1, 2, 3, or 4; X^A is selected from -CH- and -N-; X^B is selected from -CH2-, -C(R⁵¹)2-, -O-, -NH-, -N(R⁴)-, and -S-; R³³ is selected from: , , and each of which R³³ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, - OR⁷, and -SR⁷; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; R³⁸ and R³⁹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, and heterocycle each of which except hydrogen and halogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R⁴¹, R⁴², R⁴³, and R⁴⁴ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; and each R⁴⁵, R⁴⁶, and R⁴⁷ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(O)(R¹⁴)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵. A2.The compound of embodiment A1, wherein Heterocyclic Moiety^A is . A3.The compound of embodiment A2, wherein Q is NH. A4.The compound of embodiment A2, wherein Q is NCH3. A5.The compound of embodiment A2, wherein Q is CH₂. A6.The compound of embodiment A2, wherein Q is O. A7.The compound of embodiment A2, wherein Q is S. A8.The compound of embodiment A2, wherein Q is NCH2CH3. A9.The compound of embodiment A2, wherein Q is NC(O)CH3. A10. The compound of embodiment A2, wherein Q is CH(CH₃). A11. The compound of embodiment A1, wherein Heterocyclic Moiety^A is . A12. The compound of any one of embodiments A1-A11, wherein R¹ is hydrogen. A13. The compound of any one of embodiments A1-A11, wherein R¹ is CH3. A14. The compound of any one of embodiments A1-A11, wherein R¹ and R⁶ combined form a one-carbon bridge. A15. The compound of embodiment A1, wherein Heterocyclic Moiety^A is . A16. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. A17. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from , , , , , , and . A18. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are R¹² R⁵ selected from , , , , , R¹² R⁵ , , R⁵ , , , , and . A19. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from , , ,. , , and . A20. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. A21. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from , , , , , , , , , , , and . A22. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from , , , , , , , , , , , and . A23. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from , , , , , , , , , , , and . A24. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are selected from , , , , , , , , , , , and .

A25. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are A26. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. A27. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. A28. The compound of any one of embodiments A1-A15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. A29. The compound of embodiment A1, wherein Heterocyclic Moiety^A is . A30. The compound of embodiment A29, wherein R¹⁸ is , , , , , or . A31. The compound of embodiment A29, wherein R¹⁸ is , , , , , or . A32. The compound of embodiment A29, wherein R¹⁸ is , , , , , or . A33. The compound of embodiment A29, wherein R¹⁸ is , , , , , , , , , , , or . A34. The compound of embodiment A1, wherein Heterocyclic Moiety^A is . A35. The compound of embodiment A1, wherein Heterocyclic Moiety^A is . A36. The compound of any one of embodiments A29-A35, wherein R¹ is hydrogen. A37. The compound of any one of embodiments A29-A35, wherein R¹ is CH₃. A38. The compound of any one of embodiments A34-A35, wherein R¹ and R⁶ combined form a one-carbon bridge. A39. The compound of embodiment A1, wherein Heterocyclic Moiety^A is . A40. The compound of embodiment A1, wherein Heterocyclic Moiety^A is . A41. The compound of any one of embodiments A1-A40, wherein R⁶ is hydrogen. A42. The compound of any one of embodiments A1-A40, wherein R⁶ is methyl. A43. The compound of any one of embodiments A1-A42, wherein each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, and halogen. A44. The compound of any one of embodiments A1-A42, wherein each R⁵ is hydrogen. A45. The compound of any one of embodiments A1-A42, wherein one R⁵ is F. A46. The compound of any one of embodiments A1-A42, wherein R⁵ is -NR⁷R⁸ or - OR⁷. A47. The compound of embodiment A46, wherein R⁷ is hydrogen. A48. The compound of embodiment A46, wherein R⁷ is methyl. A49. The compound of any one of embodiments A46-A48, wherein R⁸ is hydrogen. A50. The compound of any one of embodiments A46-A48, wherein R⁸ is methyl. A51. The compound of any one of embodiments A1-A42, wherein R⁵ is aryl or heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. A52. The compound of any one of embodiments A1-A42, wherein R⁵ is cyano. A53. The compound of any one of embodiments A1-A42, wherein R⁵ is nitro. A54. The compound of any one of embodiments A1-A42, wherein R⁵ -C(O)CH3. A55. The compound of any one of embodiments A1-A54, wherein Linker is of formula: or . A56. The compound of embodiment A55, wherein X¹ is bond. A57. The compound of embodiment A55, wherein X¹ is heterocycle. A58. The compound of embodiment A55, wherein X¹ is NR². A59. The compound of embodiment A55, wherein X¹ is C(O). A60. The compound of any one of embodiments A55-A59, wherein X² is bond. A61. The compound of any one of embodiments A55-A59, wherein X² is heterocycle. A62. The compound of any one of embodiments A55-A59, wherein X² is NR². A63. The compound of any one of embodiments A55-A59, wherein X² is C(O). A64. The compound of any one of embodiments A55-A63, wherein R²⁰ is bond. A65. The compound of any one of embodiments A55-A63, wherein R²⁰ is CH₂. A66. The compound of any one of embodiments A55-A63, wherein R²⁰ is heterocycle. A67. The compound of any one of embodiments A55-A63, wherein R²⁰ is aryl. A68. The compound of any one of embodiments A55-A63, wherein R²⁰ is phenyl. A69. The compound of any one of embodiments A55-A63, wherein R²⁰ is bicycle. A70. The compound of any one of embodiments A55-A69, wherein R²¹ is bond. A71. The compound of any one of embodiments A55-A69, wherein R²¹ is CH2. A72. The compound of any one of embodiments A55-A69, wherein R²¹ is heterocycle. A73. The compound of any one of embodiments A55-A69, wherein R²¹ is aryl. A74. The compound of any one of embodiments A55-A69, wherein R²¹ is phenyl. A75. The compound of any one of embodiments A55-A69, wherein R²¹ is bicycle. A76. The compound of any one of embodiments A1-A54, wherein Linker is of formula: . A77. The compound of any one of embodiments A55-A76, wherein R²² is bond. A78. The compound of any one of embodiments A55-A76, wherein R²² is CH2. A79. The compound of any one of embodiments A55-A76, wherein R²² is heterocycle. A80. The compound of any one of embodiments A55-A76, wherein R²² is aryl. A81. The compound of any one of embodiments A55-A76, wherein R²² is phenyl. A82. The compound of any one of embodiments A55-A76, wherein R²² is bicycle. A83. The compound of any one of embodiments A1-A54, wherein Linker is of formula: . A84. The compound of any one of embodiments A55-A83, wherein R²³ is bond. A85. The d f f b di t A55 A83 wherein R²³ is CH2. A86. The compound of any one of embodiments A55-A83, wherein R²³ is heterocycle. A87. The compound of any one of embodiments A55-A83, wherein R²³ is aryl. A88. The compound of any one of embodiments A55-A83, wherein R²³ is phenyl. A89. The compound of any one of embodiments A55-A83, wherein R²³ is bicycle. A90. The compound of any one of embodiments A1-A54, wherein Linker is of formula: . A91. The compound of any one of embodiments A55-A90, wherein R²⁴ is bond. A92. The compound of any one of embodiments A55-A90, wherein R²⁴ is CH₂. A93. The compound of any one of embodiments A55-A90, wherein R²⁴ is heterocycle. A94. The compound of any one of embodiments A55-A90, wherein R²⁴ is aryl. A95. The compound of any one of embodiments A55-A90, wherein R²⁴ is phenyl. A96. The compound of any one of embodiments A55-A90, wherein R²⁴ is bicycle. A97. The compound of any one of embodiments A55-A90, wherein R²⁴ is C(O). A98. The compound of any one of embodiments A1-A97, wherein the KRAS Targeting Ligand^A is . A99. The compound of any one of embodiments A1-A97, wherein the KRAS Targeting Ligand^A is . A100. The compound of any one of embodiments A1-A97, wherein the KRAS Targeting Ligand^A is . A101. The compound of any one of embodiments A1-A97, wherein the KRAS Targeting Ligand^A is . A102. The compound of any one of embodiments A1-A97, wherein the KRAS Targeting Ligand^A is . A103. The compound of any one of embodiments A1-A97, wherein the KRAS Targeting Ligand^A is . A104. The compound of any one of embodiments A1-A97, wherein the KRAS Targeting Ligand^A is . A105. The compound of any one of embodiments A1-A97, wherein the KRAS Targeting Ligand^A is . A106. The compound of any one of embodiments A1-A97, wherein the KRAS Targeting Ligand^A is . A107. The compound of any one of embodiments A1-A106, wherein R³² is selected from , , , and . A108. The compound of any one of embodiments A1-A106, wherein R³² is selected from , , and . A109. The compound of any one of embodiments A1-A106, wherein R³² is selected from , , , and . A110. The compound of any one of embodiments A1-A106, wherein R³² is selected from , , , , and ; wherein: R^51B is independently selected from halogen, cyano, haloalkyl, -OR⁷, and -SR⁷; R^51C is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD3; and R^51D and R^51E are independently hydrogen, alkyl, alkenyl, haloalkyl, cyano, -OR⁷, and -SR⁷ or together with X^B and the carbon atoms to which they are attached, form a 5-, 6-, or 7- membered ring. A111. The compound of any one of embodiments A1-A106, wherein R³² is selected from and ; wherein R^51B is independently selected from halogen, cyano, haloalkyl, -OR⁷, and -SR⁷; R^51C is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD₃; and R^51D is hydrogen, alkyl, alkenyl, haloalkyl, cyano, -OR⁷, or -SR⁷; or together with X^B and the carbon atoms to which they are attached, form a 5-, 6-, or 7-membered ring. A112. The compound of any one of embodiments A1-A106, wherein R³² is . A113. The compound of embodiment A110 or embodiment A111, wherein R^51B is selected from halogen, cyano, and -OR⁷. A114. The compound of embodiment A110 or embodiment A111, wherein R^51C is selected from hydrogen, alkyl, alkynyl, cyano, and CD₃. A115. The compound of any one of embodiments A1-A114, wherein R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷. A116. The compound of any one of embodiments A1-A114, wherein R²⁹ is aryl. A117. The compound of any one of embodiments A1-A114, wherein R²⁹ is heteroaryl. A118. The compound of any one of embodiments A1-A114, wherein R²⁹ is bicycle. A119. The compound of any one of embodiments A1-A114, wherein R²⁹ is . A120. The compound of any one of embodiments A1-A119, wherein R⁴⁵ is -OR¹¹. A121. The compound of embodiment A120, wherein R¹¹ is H. A122. The compound of any one of embodiments A1-A121, wherein R⁴⁶ is selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, -OR¹¹, and C(O)R¹⁴. A123. The compound of embodiment A122, wherein R⁴⁶ is selected from alkyl, alkynyl, and halogen. A124. The compound of embodiment A122, wherein R⁴⁶ is ethyl. A125. The compound of embodiment A122, wherein R⁴⁶ is -CCH. A126. The compound of embodiment A122, wherein R⁴⁶ is chloro. A127. The compound of embodiment A122, wherein R⁴⁶ is bromo. A128. The compound of any one of embodiments A1-A127, wherein R⁴⁷ is selected from hydrogen, alkyl, haloalkyl, halogen, and -OR¹¹. A129. The compound of embodiment A128, wherein R⁴⁷ is hydrogen. A130. The compound of embodiment A128, wherein R⁴⁷ is halogen. A131. The compound of embodiment A128, wherein R⁴⁷ is fluoro. A132. The compound of embodiment A128, wherein R⁴⁷ is chloro. A133. The compound of any one of embodiments A1-A132, wherein R³³ is . A134. The compound of any one of embodiments A1-A132, wherein R³³ is , , , , , , , , , , , , or ; wherein R⁵² and R⁵⁴ are independently selected at each instance from hydrogen, halogen, cyano, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R⁵³ and R⁵⁵ are independently selected at each instance from hydrogen, halogen, cyano, alkyl, haloalkyl, -NR⁷R⁸, -OR⁷, -SR⁷, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle; and R⁵⁷ is independently selected from hydrogen, alkyl, haloalkyl, arylalkyl, C(O)R⁴, C(O)NR⁷R⁸, and R⁷. A135. The compound of embodiment A134, wherein R³³ is . A136. The compound of embodiment A134, wherein R³³ is . A137. The compound of embodiment A134, wherein R³³ is . A138. The compound of embodiment A134, wherein R³³ is . A139. The compound of embodiment A134, wherein R³³ is . A140. The compound of embodiment A134, wherein R³³ is . A141. The compound of embodiment A134, wherein R³³ is . A142. The d f b di t A134 h i R³³ is . A143. The compound of embodiment A134, wherein R³³ is . A144. The compound of embodiment A134, wherein R³³ is . A145. The compound of any one of embodiments A1-A132, wherein R³³ is selected from: , , , , and . A146. The compound of any one of embodiments A1-A132, wherein R³³ is selected from: , , , , , , , and . A147. The compound of any one of embodiments A1-A132, wherein R³³ is selected X H_3C ^N from: , , ^R8 , , , , , , , and . A148. The compound of any one of embodiments A1-A132, wherein R³³ is selected from: , , , and . A149. The compound of any one of embodiments A1-A132, wherein R³³ is . A150. The compound of any one of embodiments A1-A132, wherein R³³ is . A151. The compound of any one of embodiments A1-A150, wherein X is -O-. A152. The compound of any one of embodiments A1-A150, wherein X is -NH-. A153. The compound of any one of embodiments A1-A150, wherein X is -S-. A154. The compound of any one of embodiments A1-A132, wherein R³³ is . A155. The compound of any one of embodiments A1-A132, wherein R³³ is . A156. The compound of any one of embodiments A1-A132, wherein R³³ is . A157. The compound of any one of embodiments A1-A132, wherein R³³ is . A158. The compound of any one of embodiments A1-A132, wherein R³³ is . A159. The compound of any one of embodiments A1-A132, wherein R³³ is . A160. The compound of any one of embodiments A1-A132, wherein R³³ is . A161. The compound of any one of embodiments A1-A132, wherein R³³ is . A162. The compound of any one of embodiments A1-A132, wherein R³³ is . A163. The compound of any one of embodiments A1-A132, wherein R³³ is . A164. The compound of any one of embodiments A1-A132, wherein R³³ is . A165. The compound of any one of embodiments A1-A132, wherein R³³ is . A166. The compound of any one of embodiments A1-A132, wherein R³³ is . A167. The compound of any one of embodiments A1-A132, wherein R³³ is . A168. The compound of any one of embodiments A1-A132, wherein R³³ is . A169. The compound of any one of embodiments A1-A132, wherein R³³ is . A170. The compound of any one of embodiments A1-A132, wherein R³³ is . A171. The compound of any one of embodiments A1-A132, wherein R³³ is . A172. The compound of any one of embodiments A1-A132, wherein R³³ is . A173. The compound of any one of embodiments A1-A132, wherein R³³ is . A174. The compound of any one of embodiments A1-A132, wherein R³³ is . A175. The compound of any one of embodiments A1-A132, wherein R³³ is . A176. The compound of any one of embodiments A1-A132, wherein R³³ is . A177. The compound of any one of embodiments A1-A132, wherein R³³ is . A178. A pharmaceutical composition comprising a compound of any one of embodiments A1-A177 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. A179. The pharmaceutical composition of embodiment A178, in an oral dosage form. A180. The pharmaceutical composition of embodiment A179, wherein the oral dosage form is a solid dosage form. A181. The pharmaceutical composition of embodiment A180, wherein the dosage form is a tablet or capsule. A182. The pharmaceutical composition of embodiment A178, in a liquid dosage form. A183. The pharmaceutical composition of embodiment A182, wherein the liquid dosage form is suitable for parenteral administration. A184. The pharmaceutical composition of embodiment A182, wherein the liquid dosage form is suitable for intravenous administration. A185. The pharmaceutical composition of embodiment A182, wherein the liquid dosage form is suitable for intramuscular administration. A186. A method of treating a KRAS mediated disorder comprising administering an effective amount of a compound or pharmaceutical composition of any one of embodiments A1-A185, or a pharmaceutically acceptable salt thereof, to a human patient in need thereof. A187. The method of treatment of embodiment A186, wherein the disorder is a cancer. A188. The method of treatment of embodiment A187, wherein the cancer is mediated by a mutant form of KRAS. A189. The method of treatment of embodiment A187, wherein the cancer is mediated by KRAS G12D. A190. The method of treatment of embodiment A187, wherein the cancer is mediated by KRAS G12V. A191. The method of treatment of any one of embodiments A187-A190, wherein the compound is administered in combination with an additional anticancer compound. B1.A compound of Formula: or or a pharmaceutically acceptable salt thereof; wherein: KRAS Targeting Ligand^B is ; Heterocyclic Moiety^A is selected from: R⁶ O O NH N Q R¹ O Cycle , and ; Q is CH2, NR², , O, or S; R¹ and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R¹ and R⁶ are combined to form a one or two carbon bridge to form a fused cycle; each R² is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R⁹, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)2R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)2R⁹, -SC(O)R⁹, -OS(O)2R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, -NR⁷P(O)(R⁹)₂, and -OP(O)(R⁹)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R¹⁶ is selected from: , , , , and , and R¹², each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R¹⁷ is selected from: , , , , and , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R¹⁸ is a 9-membered heteroaryl attached to the azaglutarimide moiety through a C-N bond, optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; R¹² is the attachment point to Linker; R⁷ and R⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR⁷R⁸, -OR⁷, and -SR⁷ each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; R¹¹ and R¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2; R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; R³⁰ and R³¹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R³³ is selected from: , , and each of which R³³ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; and each R⁴⁵, R⁴⁶, and R⁴⁷ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(O)(R¹⁴)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; Linker is selected from ; wherein: X¹ and X² are independently at each occurrence selected from bond, heterocycle, NR², C(R²)₂, O, C(O), and S; R²⁰, R²¹, R²², R²³, and R²⁴ are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO₂-, -S(O)-, -C(S)-, -C(O)NR²-, -NR²C(O)-, -O-, -S-, -NR²-, -C(R⁴⁰R⁴⁰)-, -P(O)(OR²⁶)O-, -P(O)(OR²⁶)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁰; R²⁶ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle; and R⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl)₂, -NHSO₂(alkyl), -N(alkyl)SO₂alkyl, -NHSO₂(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO₂alkenyl, -NHSO₂alkynyl, -N(alkyl)SO₂alkynyl, haloalkyl, aryl, heteroaryl, heterocycle, and cycloalkyl. B2.A compound of Formula: ; or a pharmaceutically acceptable salt thereof; wherein: Heterocyclic Moiety^B is selected from: , and ; Q is CH2, NR², , O, or S; Q² is CH₂, , O, or S; R¹ and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R¹ and R⁶ are combined to form a one or two carbon bridge to form a fused cycle; each R² and R⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R⁹, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)2R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)2R⁹, -SC(O)R⁹, -OS(O)2R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, -NR⁷P(O)(R⁹)2, and -OP(O)(R⁹)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R¹⁶ is selected from: , , , , and , and R¹², each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R^16B is selected from: , , , and ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R^17B is selected from: and ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; Cycle² is a fused heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; R¹² is the attachment point to Linker; R⁷ and R⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR⁷R⁸, -OR⁷, and -SR⁷ each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; R¹¹ and R¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2 each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂; KRAS Targeting Ligand^A is selected from: , , , R⁴¹ R⁴² R³² R^{43 44} N R R²⁹ N R³³ R³⁸ R³⁹ , , , , , and ; R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; R³⁰ and R³¹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R³² is selected from: and ; wherein attachment point is attached to the Linker and the remaining attachment point is attached to the KRAS Targeting Moiety; R⁵¹ and R^51A are independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, h l it NR⁷R⁸ OR⁷ d SR⁷ R⁸⁸ is selected at each instance from aryl, heteroaryl, heterocycle, bicycle, and spirocycle; z is independently selected at each instance from 0, 1, 2, 3, or 4 as allowed by valence; q is 1, 2, 3, or 4; w is 1, 2, 3, or 4; X^A is selected from -CH- and -N-; X^B is selected from -CH₂-, -C(R⁵¹)₂-, -O-, -NH-, -N(R⁴)-, and -S-; R³³ is selected from: , , and each of which R³³ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; R³⁸ and R³⁹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, and heterocycle each of which except hydrogen and halogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R⁴¹, R⁴², R⁴³, and R⁴⁴ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; and each R⁴⁵, R⁴⁶, and R⁴⁷ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; Linker is selected from ; X¹ and X² are independently at each occurrence selected from bond, heterocycle, NR², C(R²)₂, O, C(O), and S; R²⁰, R²¹, R²², R²³, and R²⁴ are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR²-, -NR²C(O)-, -O-, -S-, -NR²-, -C(R⁴⁰R⁴⁰)-, -P(O)(OR²⁶)O-, -P(O)(OR²⁶)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁰; R²⁶ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle; and R⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl)2, -NHSO2(alkyl), -N(alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO₂(aryl, heteroaryl or heterocycle), -NHSO₂alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aryl, heteroaryl, heterocycle, and cycloalkyl. B3.The compound of embodiment B2, wherein Heterocyclic Moiety^B is selected from , , and . B4.The compound of embodiment B1, wherein Heterocyclic Moiety^A is . B5.The compound of embodiment B4 wherein Q is NH B6.The compound of embodiment B4, wherein Q is NCH₃. B7.The compound of embodiment B4, wherein Q is CH₂. B8.The compound of embodiment B4, wherein Q is O. B9.The compound of embodiment B4, wherein Q is S. B10. The compound of embodiment B4, wherein Q is NCH2CH3. B11. The compound of embodiment B1, wherein Heterocyclic Moiety^A is . B12. The compound of any one of embodiments B1-B11, wherein R¹ is hydrogen. B13. The compound of any one of embodiments B1-B11, wherein R¹ is CH₃. B14. The compound of any one of embodiments B1-B11, wherein R¹ and R⁶ combined form a one-carbon bridge. B15. The compound of embodiment B1, wherein Heterocyclic Moiety^A is . B16. The compound of any one of embodiments B4-B15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. B17. The compound of any one of embodiments B4-B15, wherein R¹⁶ and R¹⁷ are selected from , , , , , , and . B18. The compound of any one of embodiments B4-B15, wherein R¹⁶ and R¹⁷ are selected from R¹² R⁵ , , , , , , , R¹² R⁵ R⁵ , , , , and . B19. The compound of any one of embodiments B4-B15, wherein R¹⁶ and R¹⁷ are selected from , , ,. , , and . B20. The compound of any one of embodiments B4-B15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. B21. The compound of any one of embodiments B1-B2 and B4-B15, wherein R¹⁶, R^16B and R¹⁷ are selected from , , , , , , , , , , , and . B22. The compound of any one of embodiments B1-B2 and B4-B15, wherein R¹⁶, R^16B and R¹⁷ are selected from R¹² R⁵ R⁵ N , , , , , , R⁵ R¹² R⁵ R⁵ R⁵ , , , , ^R12 N , and N . B23. The compound of any one of embodiments B1-B2 and B4-B15, wherein R¹⁶, R^16B and R¹⁷ are selected from , , , , , , , , , , , and . B24. The compound of any one of embodiments B1-B2 and B4-B15, wherein R¹⁶, R^16B and R¹⁷ are selected from R⁵ N N 1² N N R R¹² , , , , , , , , , , , and . B25. The compound of any one of embodiments B1-B2 and B4-B15, wherein R¹⁶, R^16B, R¹⁷, and R^17B are selected from , , , , , and . B26. The compound of any one of embodiments B1-B2 and B4-B15, wherein R¹⁶, R^16B, R¹⁷, and R^17B are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. B27. The compound of any one of embodiments B1-B2 and B4-B15, wherein R¹⁶, R^16B, R¹⁷, and R^17B are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. B28. The compound of any one of embodiments B4-B15, wherein R¹⁶ and R¹⁷ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. B29. The compound of embodiment B1, wherein Heterocyclic Moiety^A is . B30. The compound of embodiment B29, wherein R¹⁸ is , , , , , or . B31. The compound of embodiment B29, wherein R¹⁸ is , , , , , or . B32. The compound of embodiment B29, wherein R¹⁸ is , , , , , or . B33. The compound of embodiment B29, wherein R¹⁸ is , R⁵ N N 1 N N R ^{2 12} , , , , R , , , , , , or . B34. The compound of embodiment B1 or embodiment B2, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are . B35. The compound of embodiment B1 or embodiment B2, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are . B36. The compound of any one of embodiments B34-B35, wherein R¹ is hydrogen. B37. The compound of any one of embodiments B34-B35, wherein R¹ is CH3. B38. The compound of any one of embodiments B34-B35, wherein R¹ and R⁶ combined form a one-carbon bridge. B39. The compound of embodiment B1 or embodiment B2, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are . B40. The compound of embodiment B1 or embodiment B2, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are . B41. The compound of any one of embodiments B1-B40, wherein R⁶ is hydrogen. B42. The compound of any one of embodiments B1-B40, wherein R⁶ is methyl. B43. The compound of any one of embodiments B1-B42, wherein each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, and halogen. B44. The compound of any one of embodiments B1-B42, wherein each R⁵ is hydrogen. B45. The compound of any one of embodiments B1-B42, wherein one R⁵ is F. B46. The compound of any one of embodiments B1-B42, wherein R⁵ is -NR⁷R⁸ or -OR⁷. B47. The compound of embodiment B46, wherein R⁷ is hydrogen. B48. The compound of embodiment B46, wherein R⁷ is methyl. B49. The compound of any one of embodiments B46-B48, wherein R⁸ is hydrogen. B50. The compound of any one of embodiments B46-B48, wherein R⁸ is methyl. B51. The compound of any one of embodiments B1-B42, wherein R⁵ is aryl or heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. B52. The compound of any one of embodiments B1-B42, wherein R⁵ is cyano. B53. The compound of any one of embodiments B1-B42, wherein R⁵ is nitro. B54. The compound of any one of embodiments B1-B42 wherein R⁵ -C(O)CH₃. B55. The compound of any one of embodiments B1-B54, wherein Linker is of formula: or . B56. The compound of embodiment B55, wherein X¹ is bond. B57. The compound of embodiment B55, wherein X¹ is heterocycle. B58. The compound of embodiment B55, wherein X¹ is NR². B59. The compound of embodiment B55, wherein X¹ is C(O). B60. The compound of any one of embodiments B55-B59, wherein X² is bond. B61. The compound of any one of embodiments B55-B59, wherein X² is heterocycle. B62. The compound of any one of embodiments B55-B59, wherein X² is NR². B63. The compound of any one of embodiments B55-B59, wherein X² is C(O). B64. The compound of any one of embodiments B55-B63, wherein R²⁰ is bond. B65. The compound of any one of embodiments B55-B63, wherein R²⁰ is CH₂. B66. The compound of any one of embodiments B55-B63, wherein R²⁰ is heterocycle. B67. The compound of any one of embodiments B55-B63, wherein R²⁰ is aryl. B68. The compound of any one of embodiments B55-B63, wherein R²⁰ is phenyl. B69. The compound of any one of embodiments B55-B63, wherein R²⁰ is bicycle. B70. The compound of any one of embodiments B55-B69, wherein R²¹ is bond. B71. The compound of any one of embodiments B55-B69, wherein R²¹ is CH₂. B72. The compound of any one of embodiments B55-B69, wherein R²¹ is heterocycle. B73. The compound of any one of embodiments B55-B69, wherein R²¹ is aryl. B74. The compound of any one of embodiments B55-B69, wherein R²¹ is phenyl. B75. The compound of any one of embodiments B55-B69, wherein R²¹ is bicycle. B76. The compound of any one of embodiments B1-B54, wherein Linker is of formula: . B77. The compound of any one of embodiments B55-B76, wherein R²² is bond. B78. The compound of any one of embodiments B55-B76, wherein R²² is CH2. B79. The compound of any one of embodiments B55-B76, wherein R²² is heterocycle. B80. The compound of any one of embodiments B55-B76 wherein R²² is aryl. B81. The compound of any one of embodiments B55-B76, wherein R²² is phenyl. B82. The compound of any one of embodiments B55-B76, wherein R²² is bicycle. B83. The compound of any one of embodiments B1-B54, wherein Linker is of formula: . B84. The compound of any one of embodiments B55-B83, wherein R²³ is bond. B85. The compound of any one of embodiments B55-B83, wherein R²³ is CH2. B86. The compound of any one of embodiments B55-B83, wherein R²³ is heterocycle. B87. The compound of any one of embodiments B55-B83, wherein R²³ is aryl. B88. The compound of any one of embodiments B55-B83, wherein R²³ is phenyl. B89. The compound of any one of embodiments B55-B83, wherein R²³ is bicycle. B90. The compound of any one of embodiments B1-B54, wherein Linker is of formula: . B91. The compound of any one of embodiments B55-B90, wherein R²⁴ is bond. B92. The compound of any one of embodiments B55-B90, wherein R²⁴ is CH₂. B93. The compound of any one of embodiments B55-B90, wherein R²⁴ is heterocycle. B94. The compound of any one of embodiments B55-B90, wherein R²⁴ is aryl. B95. The compound of any one of embodiments B55-B90, wherein R²⁴ is phenyl. B96. The compound of any one of embodiments B55-B90, wherein R²⁴ is bicycle. B97. The compound of any one of embodiments B55-B90, wherein R²⁴ is C(O). B98. The compound of any one of embodiments B2-B97, wherein the KRAS Targeting Ligand^A is . B99. The compound of any one of embodiments B2-B97, wherein the KRAS Targeting Ligand^A is . B100. The compound of any one of embodiments B2-B97, wherein the KRAS Targeting Ligand^A is . B101. The compound of any one of embodiments B2-B97, wherein the KRAS Targeting Ligand^A is . B102. The compound of any one of embodiments B2-B97, wherein the KRAS Targeting Ligand^A is . B103. The compound of any one of embodiments B2-B97, wherein the KRAS Targeting Ligand^A is . B104. The compound of any one of embodiments B2-B97, wherein the KRAS Targeting Ligand^A is . B105. The compound of any one of embodiments B2-B97, wherein the KRAS Targeting Ligand^A is . B106. The compound of any one of embodiments B2-B97, wherein the KRAS Targeting Ligand^A is . B107. The compound of any one of embodiments B2-B106, wherein R³² is selected from , , , and . B108. The compound of any one of embodiments B2-B106, wherein R³² is selected from , , and . B109. The compound of any one of embodiments B2-B106, wherein R³² is selected from , , , and .

B110. The compound of any one of embodiments B2-B106, wherein R³² is selected from , , , , and ; wherein: R^51B is independently selected from halogen, cyano, haloalkyl, -OR⁷, and -SR⁷; R^51C is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD₃; and R^51D and R^51E are independently hydrogen, alkyl, alkenyl, haloalkyl, cyano, -OR⁷, and -SR⁷ or together with X^B and the carbon atoms to which they are attached, form a 5-, 6-, or 7- membered ring. B111. The compound of any one of embodiments B2-B106, wherein R³² is selected from and ; wherein R^51B is independently selected from halogen, cyano, haloalkyl, -OR⁷, and -SR⁷; R^51C is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD3. B112. The compound of any one of embodiments B2-B106, wherein R³² is . B113. The compound of embodiment B110 or embodiment B111, wherein R^51B is selected from halogen, cyano, and -OR⁷. B114. The compound of embodiment B110 or embodiment B111, wherein R^51C is selected from hydrogen, alkyl, alkynyl, cyano, and CD₃. B115. The compound of any one of embodiments B1-B114, wherein R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷. B116. The compound of any one of embodiments B1-B114, wherein R²⁹ is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷. B117. The compound of any one of embodiments B1-B114, wherein R²⁹ is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷. B118. The compound of any one of embodiments B1-B114, wherein R²⁹ is bicycle optionally substituted with 1, 2, or 3 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷. B119. The compound of any one of embodiments B1-B114, wherein R²⁹ is . B120. The compound of any one of embodiments B1-B119, wherein R⁴⁵ is - OR¹¹. B121. The compound of embodiment B120, wherein R¹¹ is H. B122. The compound of any one of embodiments B1-B121, wherein R⁴⁶ is selected from alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, -OR¹¹, and C(O)R¹⁴ B123. The compound of embodiment B122, wherein R⁴⁶ is selected from alkyl, alkynyl, and halogen. B124. The compound of embodiment B122, wherein R⁴⁶ is ethyl. B125. The compound of embodiment B122, wherein R⁴⁶ is -CCH. B126. The compound of embodiment B122, wherein R⁴⁶ is chloro. B127. The compound of embodiment B122, wherein R⁴⁶ is bromo. B128. The compound of any one of embodiments 1-127, wherein R⁴⁷ is selected from hydrogen, alkyl, haloalkyl, halogen, and -OR¹¹. B129. The compound of embodiment B128, wherein R⁴⁷ is hydrogen. B130. The compound of embodiment B128, wherein R⁴⁷ is halogen. B131. The compound of embodiment B128, wherein R⁴⁷ is fluoro. B132. The compound of embodiment B128, wherein R⁴⁷ is chloro. B133. The compound of any one of embodiments B1-B132, wherein R³³ is . B134. The compound of any one of embodiments B1-B132, wherein R³³ is , , , , , , , , , , , or ; wherein R⁵² and R⁵⁴ are independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R⁵³ and R⁵⁵ are independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, -NR⁷R⁸, -OR⁷, -SR⁷, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; and and R⁵⁷ is independently selected from hydrogen, alkyl, haloalkyl, arylalkyl, C(O)NR⁷R⁸, and R⁷. B135. The compound of embodiment B134, wherein R³³ is . B136. The compound of embodiment B134, wherein R³³ is . B137. The compound of embodiment B134, wherein R³³ is . B138. The compound of embodiment B134, wherein R³³ is . B139. The compound of embodiment B134, wherein R³³ is . B140. The compound of embodiment B134, wherein R³³ is . B141. The compound of embodiment B134, wherein R³³ is . B142. The compound of embodiment B134, wherein R³³ is . B143. The compound of embodiment B134, wherein R³³ is . B144. The compound of embodiment B134, wherein R³³ is . B145. The compound of any one of embodiments B1-B132, wherein R³³ is selected from: , , , and . B146. The compound of any one of embodiments B1-B132, wherein R³³ is selected from: , , , , , , , and . B147. The compound of any one of embodiments B1-B132, wherein R³³ is selected from: , , X H_3C ^{N R8} , , , , , , , and . B148. The compound of any one of embodiments B1-B132, wherein R³³ is selected from: , , , and . B149. The compound of any one of embodiments B1-B132, wherein R³³ is . B150. The compound of any one of embodiments B1-B132, wherein R³³ is . B151. The compound of any one of embodiments B1-B150, wherein X is -O-. B152. The compound of any one of embodiments B1-B150, wherein X is -NH-. B153. The compound of any one of embodiments B1-B150, wherein X is -S-. B154. The compound of any one of embodiments B1-B132, wherein R³³ is . B155. The compound of any one of embodiments B1-B132, wherein R³³ is . B156. The compound of any one of embodiments B1-B132, wherein R³³ is . B157. The compound of any one of embodiments B1-B132, wherein R³³ is . B158. The compound of any one of embodiments B1-B132, wherein R³³ is . B159. The compound of any one of embodiments B1-B132, wherein R³³ is . B160. The compound of any one of embodiments B1-B132, wherein R³³ is . B161. The compound of any one of embodiments B1-B132, wherein R³³ is . B162. The compound of any one of embodiments B1-B132, wherein R³³ is . B163. The compound of any one of embodiments B1-B132, wherein R³³ is . B164. The compound of any one of embodiments B1-B132, wherein R³³ is . B165. The compound of any one of embodiments B1-B132, wherein R³³ is . B166. The compound of any one of embodiments B1-B132, wherein R³³ is . B167. The compound of any one of embodiments B1-B132, wherein R³³ is . B168. The compound of any one of embodiments B1-B132, wherein R³³ is . B169. The compound of any one of embodiments B1-B132, wherein R³³ is . B170. The compound of any one of embodiments B1-B132, wherein R³³ is . B171. The compound of any one of embodiments B1-B132, wherein R³³ is . B172. The compound of any one of embodiments B1-B132, wherein R³³ is . B173. The compound of any one of embodiments B1-B132, wherein R³³ is . B174. The compound of any one of embodiments B1-B132, wherein R³³ is . B175. The compound of any one of embodiments B1-B132, wherein R³³ is . B176. The compound of any one of embodiments B1-B132, wherein R³³ is . B177. The compound of any one of embodiments B1-B132, wherein R³³ is . B178. A pharmaceutical composition comprising a compound of any one of embodiments B1-B177 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. B179. The pharmaceutical composition of embodiment B178, in an oral dosage form. B180. The pharmaceutical composition of embodiment B179, wherein the oral dosage form is a solid dosage form. B181. The pharmaceutical composition of embodiment B180, wherein the dosage form is a tablet or capsule. B182. The pharmaceutical composition of embodiment B178, in a liquid dosage form. B183. The pharmaceutical composition of embodiment B182, wherein the liquid dosage form is suitable for parenteral administration. B184. The pharmaceutical composition of embodiment B182, wherein the liquid dosage form is suitable for intravenous administration. B185. The pharmaceutical composition of embodiment B182, wherein the liquid dosage form is suitable for intramuscular administration. B186. A method of treating a KRAS mediated disorder comprising administering an effective amount of a compound or pharmaceutical composition of any one of embodiments B1-B185, or a pharmaceutically acceptable salt thereof, to a human patient in need thereof. B187. The method of treatment of embodiment B186, wherein the disorder is a cancer. B188. The method of treatment of embodiment B187, wherein the cancer is mediated by a mutant form of KRAS. B189. The method of treatment of embodiment B187, wherein the cancer is mediated by KRAS G12D. B190. The method of treatment of embodiment B187, wherein the cancer is mediated by KRAS G12V. B191. The method of treatment of any one of embodiments B187-B190, wherein the compound is administered in combination with an additional anticancer compound. B192. Use of a compound of any one of embodiments B1-B185, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a KRAS mediated disorder. B193. Use of a compound of any one of embodiments B1-B185, or a pharmaceutically acceptable salt thereof, in the treatment of a KRAS mediated disorder. B194. The use of embodiment B192 or B193, wherein the disorder is a cancer. B195. The use of embodiment B194, wherein the cancer is mediated by a mutant form of KRAS. B196. The use of embodiment B194, wherein the cancer is mediated by KRAS G12D. B197. The use of embodiment B194, wherein the cancer is mediated by KRAS G12V. C1.A compound of Formula: or a pharmaceutically acceptable salt thereof; wherein: KRAS Targeting Ligand^B is ; Heterocyclic Moiety^A is selected from: , and ; Q is CH2, NR², , O, or S; R¹ and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R¹ and R to form a fused cycle; each R² is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R⁹, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)₂R⁹, -SC(O)R⁹, -OS(O)₂R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)2R⁹, -P(O)(R⁹)2, -SP(O)(R⁹)2, -NR⁷P(O)(R⁹)₂, and -OP(O)(R⁹)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R¹⁶ is selected from: , , , , and , and R¹², each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R¹⁷ is selected from: , , , , and , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R¹⁸ is a 9-membered heteroaryl attached to the azaglutarimide moiety through a C-N bond, optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; R¹² is the attachment point to Linker; R⁷ and R⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR⁷R⁸, -OR⁷, and -SR⁷ each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; R¹¹ and R¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂; R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; R³⁰ and R³¹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, ni d R³³ is selected from: , , and each of which R³³ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; and each R⁴⁵, R⁴⁶, and R⁴⁷ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; Linker is selected from ; wherein: X¹ and X² are independently at each occurrence selected from bond, heterocycle, NR², C(R²)2, O, C(O), and S; R²⁰, R²¹, R²², R²³, and R²⁴ are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR²-, -NR²C(O)-, -O-, -S-, -NR²-, -C(R⁴⁰R⁴⁰)-, -P(O)(OR²⁶)O-, -P(O)(OR²⁶)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁰; R²⁶ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle; and R⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl)2, -NHSO2(alkyl), -N(alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aryl, heteroaryl, heterocycle, and cycloalkyl. C2.A compound of Formula: ; or a pharmaceutically acceptable salt thereof; wherein: Heterocyclic Moiety^B is selected from: , and ; Q is CH₂, NR², , O, or S; Q² is CH₂, , O, or S; R¹ and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R¹ and R⁶ are combined to form a one or two carbon bridge to form a fused cycle; each R² and R⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R⁹, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)2R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)2R⁹, -SC(O)R⁹, -OS(O)2R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, - NR⁷P(O)(R⁹)2, and -OP(O)(R⁹)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R¹⁶ is selected from: , , , , and , and R¹², each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R^16B is selected from: , , , and ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R^17B is selected from: and ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; Cycle² is a fused heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; R¹² is the attachment point to Linker; R⁷ and R⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR⁷R⁸, -OR⁷, and -SR⁷ each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; R¹¹ and R¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(O)(R¹⁴)₂; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2; KRAS Targeting Ligand^A is selected from: , , 4^{1 42} R^{32 43} R R R 4 N R ⁴ R²⁹ N R³³ , R³⁸ R³⁹ , , , , , and ; R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; R³⁰ and R³¹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R³² is selected from: and ; wherein attachment point is attached to the Linker and the remaining attachment point is attached to the KRAS Targeting Moiety; R⁵¹ and R^51A are independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R⁸⁸ is selected at each instance from aryl, heteroaryl, heterocycle, bicycle, and spirocycle; z is independently selected at each instance from 0, 1, 2, 3, or 4 as allowed by valence; q is 1, 2, 3, or 4; w is 1, 2, 3, or 4; X^A is selected from -CH- and -N-; X^B is selected from -CH₂-, -C(R⁵¹)₂-, -O-, -NH-, -N(R⁴)-, and -S-; R³³ is selected from: , , and each of which R³³ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; R³⁸ and R³⁹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, and heterocycle each of which except hydrogen and halogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R⁴¹, R⁴², R⁴³, and R⁴⁴ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; and each R⁴⁵, R⁴⁶, and R⁴⁷ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)2R¹⁴, and -P(O)(R¹⁴)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; Linker is selected from ; X¹ and X² are independently at each occurrence selected from bond, heterocycle, NR², C(R²)₂, O, C(O), and S; R²⁰, R²¹, R²², R²³, and R²⁴ are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO₂-, -S(O)-, -C(S)-, -C(O)NR²-, -NR²C(O)-, -O-, -S-, -NR²-, -C(R⁴⁰R⁴⁰)-, -P(O)(OR²⁶)O-, -P(O)(OR²⁶)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁰; R²⁶ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle; and R⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl)₂, -NHSO₂(alkyl), -N(alkyl)SO₂alkyl, -NHSO₂(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO₂alkenyl, -NHSO₂alkynyl, -N(alkyl)SO₂alkynyl, haloalkyl, aryl, heteroaryl, heterocycle, and cycloalkyl.

C3.The compound of embodiment C2, wherein Heterocyclic Moiety^B is selected from , , and . C4.The compound of embodiment C1, wherein Heterocyclic Moiety^A is . C5.The compound of embodiment C4, wherein Q is NH, NCH₃, O, or S. C6.The compound of embodiment C1, wherein Heterocyclic Moiety^A is . C7.The compound of any one of embodiments C1-C6, wherein R¹ is hydrogen. C8.The compound of any one of embodiments C1 and C4-C7, wherein R¹⁶ and R¹⁷ are selected from , , , , , and . C9.The compound of any one of embodiments C1-C2 and C4-C7, wherein R¹⁶, R^16B and R¹⁷ are selected from , , , , , N N , _R ^{12 R}2 , , , , , . , , , , , and . C10. The compound of embodiment C1, wherein Heterocyclic Moiety^A is . C11. The compound of embodiment C10, wherein R¹⁸ is , , , , , , , , , , , , , , N N , _R ^{12 R}2 , , or . C12. The compound of embodiment C1 or embodiment C2, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are or C13. The compound of any one of embodiments C1-C12, wherein R⁶ is hydrogen. C14. The compound of any one of embodiments C1-C13, wherein each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, and halogen. C15. The compound of any one of embodiments C1-C14, wherein Linker is of formula: . C16. The compound of any one of embodiments C1-C15, wherein X¹ is bond, heterocycle, or -NR²-. C17. The compound of any one of embodiments C1-C16, wherein R²³ is bond, heterocycle, or -NR²-. C18. The compound of any one of embodiments C1-C17, wherein R²⁰ is alkyl, heterocycle, aryl, heteroaryl or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R⁴⁰. C19. The compound of any one of embodiments C1-C18, wherein R²¹ is bond, -O-, -NR²-, -S-, alkyl, heterocycle, aryl, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R⁴⁰. C20. The compound of any one of embodiments C1-C19, wherein R²² is alkyl, heterocycle, aryl, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R⁴⁰. C21. The compound of any one of embodiments C2-C20, wherein the KRAS Targeting Ligand^A is . C22. The compound of any one of embodiments C2-C21, wherein R³² is selected from , , , , and ; wherein: R^51B is independently selected from halogen, cyano, haloalkyl, -OR⁷, and -SR⁷; R^51C is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD3; and R^51D and R^51E are independently hydrogen, alkyl, alkenyl, haloalkyl, cyano, -OR⁷, and -SR⁷ or together with X^B and the carbon atoms to which they are attached, form a 5-, 6-, or 7- membered ring. C23. The compound of any one of embodiments C1-C22, wherein R²⁹ is . C24. The compound of any one of embodiments C1-C23, wherein R³³ is , , , , , , , , , or ; wherein R⁵² and R⁵⁴ are independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R⁵³ and R⁵⁵ are independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, -NR⁷R⁸, -OR⁷, -SR⁷, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; and R⁵⁷ is independently selected from hydrogen, alkyl, haloalkyl, arylalkyl, C(O)R⁴, C(O)NR⁷R⁸, and R⁷. C25. The compound of embodiment C1 or embodiment C2, wherein the compound is selected from the compounds of Table 3B or a pharmaceutically acceptable salt thereof. C26. A compound of Table 3A or a pharmaceutically acceptable salt thereof. C27. A pharmaceutical composition comprising a compound of any one of embodiments C1-C26, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. C28. The pharmaceutical composition of embodiment C27 for the treatment of a KRAS mediated cancer. C29. A method of treating a KRAS mediated cancer comprising administering an effective amount of a compound of any one of embodiments C1-C26 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to a human patient in need thereof. C30. Use of a compound of any one of embodiments C1-C26 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the treatment of a KRAS mediated cancer. C31. Use of a compound of any one of embodiments C1-C26 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament to treat a KRAS mediated cancer. EMBODIMENTS OF FORMULA IA AND FORMULA IB In certain embodiments, the compound of the present invention is of Formula: , , , , , , , , , , , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: R⁶ O R¹ O HN N N R² O Cycle KRAS Linker Targeting Ligand^B or or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , 10 , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: 5 , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , 0 , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , , , , , , , , , , , , , , , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , O R⁵ HN KRAS O O heteroaryl Linker Targeting , ^LigandA , , , , , , , O HN F R¹ KRAS O O Linker Targeting , ^LigandA , O HN R⁵ KRAS O O Linker Targeting , ^LigandA , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: 5 , , , , , , , , , , , , , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , or or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , or or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , , , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , , ,or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , or . or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , , , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is of Formula: , 5 , , or , or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from: , , or , or a pharmaceutically acceptable salt thereof. Embodiments of R¹ and R⁶ In certain embodiments R¹ is hydrogen. In certain embodiments R¹ is alkyl. In certain embodiments R¹ is halogen. In certain embodiments, R¹ is halogen, wherein the halogen is F. In certain embodiments, R¹ is halogen, wherein the halogen is Cl. In certain embodiments, R¹ is halogen, wherein the halogen is Br. In certain embodiments, R¹ is halogen, wherein the halogen is I. In certain embodiments R⁶ is alkyl. In certain embodiments R⁶ is haloalkyl. In certain embodiments R¹ and R⁶ are combined to form a single carbon bridge. In certain embodiments R¹ and R⁶ are both hydrogen. Embodiments of R² In certain embodiments R² is hydrogen. In certain embodiments R² is alkyl. In certain embodiments R² is haloalkyl. In certain embodiments R² is alkenyl. In certain embodiments R² is alkynyl. In certain embodiments R² is aryl. In certain embodiments, R² is aryl, wherein the aryl is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments, R² is phenyl. In certain embodiments, R² is phenyl substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments R² is heteroaryl. In certain embodiments, R² is heteroaryl, wherein the heteroaryl is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments R² is heterocycle. In certain embodiments, R² is heterocycle, wherein the heterocycle is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments R² is C(O)R⁹. In certain embodiments, R² is C(O)R⁹, wherein C(O)R⁹ is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments R¹, R², and R⁶ are each hydrogen. Embodiments of R⁴ In certain embodiments R⁴ is hydrogen. In certain embodiments R⁴ is alkyl. In certain embodiments R⁴ is haloalkyl. In certain embodiments R⁴ is alkenyl. In certain embodiments R⁴ is alkynyl. In certain embodiments R⁴ is aryl. In certain embodiments, R⁴ is aryl, wherein the aryl is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments, R⁴ is phenyl. In certain embodiments, R⁴ is phenyl substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments R⁴ is heteroaryl. In certain embodiments, R⁴ is heteroaryl, wherein the heteroaryl is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments R⁴ is heterocycle. In certain embodiments, R⁴ is heterocycle, wherein the heterocycle is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments R⁴ is C(O)R⁹. In certain embodiments, R⁴ is C(O)R⁹, wherein C(O)R⁹ is substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰. In certain embodiments R¹, R², R⁴, and R⁶ are each hydrogen. Embodiments of R⁵ In certain embodiments R⁵ is hydrogen. In certain embodiments each R⁵ is selected from alkyl, haloalkyl, and halogen. In certain e b di i lk l In certain embodiments R⁵ is haloalkyl. In certain embodiments R⁵ is alkenyl. In certain embodiments R⁵ is alkynyl. In certain embodiments R⁵ is halogen. In certain embodiments, R⁵ is halogen, wherein the halogen is F. In certain embodiments, R⁵ is halogen, wherein the halogen is Cl. In certain embodiments, R⁵ is halogen, wherein the halogen is Br. In certain embodiments, R⁵ is halogen, wherein the halogen is I. In certain embodiments R⁵ is heteroaryl. In certain embodiments, R⁵ is aryl. In certain embodiments, R⁵ is heterocycle. In certain embodiments R⁵ is cyano. In certain embodiments R⁵ is -NR⁷R⁸. In certain embodiments, R⁵ is -NR⁷C(O)R⁹. In certain embodiments, R⁵ is -NR⁷C(S)R⁹. In certain embodiments, R⁵ is -NR⁷C(O)R⁹. In certain embodiments, R⁵ is -NR⁷S(O)2R⁹. In certain embodiments R⁵ is -OR^7-. In certain embodiments R⁵ is -SR⁷. In certain embodiments, R⁵ is -S(O)2R⁹. In certain embodiments R⁵ is -C(O)R⁹. Embodiments of R⁷ and R⁸ In certain embodiments R⁷ is hydrogen. In certain embodiments R⁷ is alkyl. In certain embodiments R⁷ is methyl. In certain embodiments R⁷ is haloalkyl. In certain embodiments R⁷ is CF₃. In certain embodiments R⁷ is aryl. In certain embodiments R⁷ is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. In certain embodiments R⁷ is heteroaryl. In certain embodiments R⁷ is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. In certain embodiments R⁷ is heterocycle. In certain embodiments R⁷ is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. In certain embodiments R⁷ is C(O)R¹⁴. In certain embodiments R⁷ is C(O) alkyl. In certain embodiments R⁸ is hydrogen. In certain embodiments R⁸ is alkyl. In certain e b di i h l In certain embodiments R⁸ is haloalkyl. In certain embodiments R⁸ is CF₃. In certain embodiments R⁷ and R⁸ are both hydrogen. Embodiments of R⁹ In certain embodiments R⁹ is hydrogen. In certain embodiments R⁹ is alkyl. In certain embodiments R⁹ is methyl. In certain embodiments R⁹ is ethyl. In certain embodiments R⁹ is haloalkyl. In certain embodiments R⁹ is CF3. In certain embodiments R⁹ is aryl. In certain embodiments R⁹ is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. In certain embodiments R⁹ is heteroaryl. In certain embodiments R⁹ is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. In certain embodiments R⁹ is heterocycle. In certain embodiments R⁹ is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁰. In certain embodiments R⁹ is -NR⁷R⁸. In certain embodiments R⁹ is -NH₂. In certain embodiments R⁹ is -N(CH3)H. In certain embodiments R⁹ is -N(CH₃)₂. In certain embodiments R⁹ is -OR⁷. In certain embodiments R⁹ is -OH. In certain embodiments R⁹ is -SR⁷. In certain embodiments R⁹ is -SH. Embodiments of R¹⁰ In certain embodiments R¹⁰ is hydrogen. In certain embodiments R¹⁰ is alkyl. In certain embodiments R¹⁰ is methyl. In certain embodiments R¹⁰ is ethyl. In certain embodiments R¹⁰ is haloalkyl. In certain embodiments R¹⁰ is CF3. In certain embodiments R¹⁰ is aryl. In certain embodiments R¹⁰ is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵. In certain embodiments R¹⁰ is heteroaryl. In certain embodiments R¹⁰ is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵. In certain embodiments R¹⁰ is heterocycle. In certain embodiments R¹⁰ is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵. In certain embodiments R¹⁰ is -NR¹¹R¹³. In certain embodiments R¹⁰ is -NH₂. In certain embodiments R¹⁰ is -N(CH3)H. 0 In certain embodiments R¹⁰ is -N(CH₃)₂. In certain embodiments R¹⁰ is -OR¹¹. In certain embodiments R¹⁰ is -OH. In certain embodiments R¹⁰ is -SR¹¹. In certain embodiments R¹⁰ is -SH. In certain embodiments R¹⁰ is alkenyl. In certain embodiments R¹⁰ is alkynyl. In certain embodiments R¹⁰ is cyano. In certain embodiments R¹⁰ is nitro. In certain embodiments R¹⁰ is -C(O)R¹⁴. 20 In certain embodiments R¹⁰ is -C(O)alkyl. In certain embodiments R¹⁰ is -C(O)N(alkyl)₂. In certain embodiments R¹⁰ is -C(O)N(H)(alkyl). In certain embodiments R¹⁰ is -C(S)R¹⁴. In certain embodiments R¹⁰ is -C(S)alkyl. In certain embodiments R¹⁰ is -C(S)N(alkyl)₂. In certain embodiments R¹⁰ is -C(S)N(H)(alkyl). In certain embodiments R¹⁰ is -S(O)R¹⁴. In certain embodiments R¹⁰ is -S(O)₂R¹⁴. In certain embodiments R¹⁰ is -P(O)(R¹⁴)2. Embodiments of R¹¹ and R¹³ In certain embodiments R¹¹ is hydrogen. In certain embodiments R¹¹ is alkyl. In certain e b di i h l In certain embodiments R¹¹ is haloalkyl. In certain embodiments R¹¹ is CF₃. In certain embodiments R¹¹ is aryl. In certain embodiments R¹¹ is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵. In certain embodiments R¹¹ is heteroaryl. In certain embodiments R¹¹ is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵. In certain embodiments R¹¹ is heterocycle. In certain embodiments R¹¹ is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵. In certain embodiments R¹¹ is C(O)R¹⁴. In certain embodiments R¹¹ is C(O)alkyl. In certain embodiments R¹³ is hydrogen. In certain embodiments R¹³ is alkyl. In certain embodiments R¹³ is methyl. In certain embodiments R¹³ is haloalkyl. In certain embodiments R¹³ is CF3. Embodiments of R¹⁴ In certain embodiments R¹⁴ is hydrogen. In certain embodiments R¹⁴ is alkyl. In certain embodiments R¹⁴ is methyl. In certain embodiments R¹⁴ is ethyl. In certain embodiments R¹⁴ is haloalkyl. In certain embodiments R¹⁴ is CF3. In certain embodiments R¹⁴ is aryl. In certain embodiments R¹⁴ is aryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵. In certain embodiments R¹⁴ is heteroaryl. In certain embodiments R¹⁴ is heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵. In certain embodiments R¹⁴ is heterocycle. In certain embodiments R¹⁴ is heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from R¹⁵. In certain embodiments R¹⁴ is -NH2. In certain embodiments R¹⁴ is -N(H)(alkyl). In certain embodiments R¹⁴ is -N(alkyl)2. In certain embodiments R¹⁴ is -OH. In certain embodiments R¹⁴ is alkoxy. Embodiments of R¹⁵ In certain embodiments R¹⁵ is hydrogen. In certain embodiments each R¹⁵ is selected from alkyl, haloalkyl, and halogen. In certain embodiments R¹⁵ is alkyl. In certain embodiments R¹⁵ is haloalkyl. In certain embodiments R¹⁵ is alkenyl. In certain embodiments R¹⁵ is alkynyl. In certain embodiments R¹⁵ is halogen. In certain embodiments R¹⁵ is aryl. In certain embodiments R¹⁵ is heteroaryl. In certain embodiments R¹⁵ is heterocycle. In certain embodiments R¹⁵ is cyano. In certain embodiments R¹⁵ is nitro. In certain embodiments R¹⁵ is amino. In certain embodiments R¹⁵ is hydroxyl. In certain embodiments R¹⁵ is alkoxy. In certain embodiments R¹⁵ is -N(H)(alkyl). In certain embodiments R¹⁵ is -N(alkyl)₂. Embodiments of Cycle-A and Cycle-B In certain embodiments Cycle-A is phenyl optionally substituted with 1 or 2 substituents independently selected from R⁵. In certain embodiments Cycle-A is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from R⁵. In certain embodiments Cycle-A is a 5- to 8-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from R⁵. In certain embodiments Cycle-A is a 5- to 8-membered cycloalkyl optionally substituted with 1 or 2 substituents independently selected from R⁵. In certain embodiments Cycle-A is a 5- to 8-membered cycloalkenyl optionally substituted with 1 or 2 substituents independently selected from R⁵. In certain embodiments Cycle-A is phenyl. In certain embodiments Cycle-A is a 5- or 6-membered heteroaryl. In certain embodiments Cycle-A is a 5- to 8-membered heterocycle. In certain embodiments Cycle-A is a 5- to 8-membered cycloalkyl. In certain embodiments Cycle-A is a 5- to 8-membered cycloalkenyl. In certain embodiments Cycle-B is phenyl optionally substituted with 1 or 2 substituents independently selected from R⁵. In certain embodiments Cycle-B is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from R⁵. In certain embodiments Cycle-B is a 5- to 8-membered heterocycle optionally substituted with 1 or 2 substituents independently selected from R⁵. In certain embodiments Cycle-B is a 5- to 8-membered cycloalkyl optionally substituted with 1 or 2 substituents independently selected from R⁵. In certain embodiments Cycle-B is a 5- to 8-membered cycloalkenyl optionally substituted with 1 or 2 substituents independently selected from R⁵. In certain embodiments Cycle-B is phenyl. In certain embodiments Cycle-B is a 5- or 6-membered heteroaryl. In certain embodiments Cycle-B is a 5- to 8-membered heterocycle. In certain embodiments Cycle-B is a 5- to 8-membered cycloalkyl. In certain embodiments Cycle-B is a 5- to 8-membered cycloalkenyl. In certain embodiments Cycle-A is phenyl optionally substituted with 1 or 2 substituents independently selected from R⁵ and Cycle-B is phenyl. In certain embodiments Cycle-B is phenyl optionally substituted with 1 or 2 substituents independently selected from R⁵ and Cycle-A is phenyl. In certain embodiments Cycle-A and Cycle-B are both phenyl. Embodiments of Spirocycle In certain embodiments spirocycle is a cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent. In certain embodiments cycloalkene is a cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent. In certain embodiments heterocycle is a cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent. In certain embodiments spirocycle is piperidine optionally substituted with 1, 2, 3, or 4 substituents indepe d l l d f d b i d i h R¹² substituent. In certain embodiments spirocycle is a pyrrolidine optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent. Embodiments of R³² In certain embodiments R³² is . In certain embodiments R³² is . In certain embodiments R³² is . In certain embodiments R³² is . In certain embodiments R³² is . In certain embodiments R³² is . In certain embodiments R³² is . In certain embodiments R³² is . In certain embodiments R³² is In certain embodiments R³² is and ; and R⁵⁷ is independently selected from hydrogen, alkyl, haloalkyl, arylalkyl, C(O)NR⁷R⁸, and R⁷. Embodiments of R¹⁶, R¹⁷, and R¹⁸ In certain embodiments R¹⁶ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁶ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁶ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁶ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain e b di R¹⁶ i R¹² In certain embodiments R¹⁶ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁷ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁷ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁷ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁷ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁷ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁸ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁸ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁸ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁸ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁸ is which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵. In certain embodiments R¹⁶ and R¹⁷ are selected from , , , , , , , , , , , and . In certain embodiments R¹⁶ and R¹⁷ are selected from , , , , , , , , , , , and . In certain embodiments R¹⁶ and R¹⁷ are selected from , , , , , and . In certain embodiments R¹⁸ is selected from , , , , , , , , , , , and . In certain embodiments R¹⁸ is selected from , , , , , , , , , , , and . In certain embodiments is selected from , , , , , , and . In certain embodiments is selected from R¹² R⁵ , , , , , , , , , , , and . In certain embodiments is selected from , , ,. , , and . In certain embodiments is selected from , , , , , , , , , , , and . In certain embodiments is selected from , , , and . In certain embodiments or is selected from , wherein each Y is independently selected from N, CH, or CR⁵, wherein 0, 1, or 2 (as context allows) instances of Y are selected to be N and are selected to produce a stable ring as well known to those skilled in the art and that forms a pharmaceutically acceptable compound. In certain embodiments or is selected from , wherein each Y is independently selected from N, CH, or CR⁵, wherein 0, 1, or 2, (as context allows) instances of Y are selected to be N and are selected to produce a stable ring as well known to those skilled in the art and that forms a pharmaceutically acceptable compound. Non-limiting examples of include the following: , , , , , and . Additional examples of include the following: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . In certain embodiments is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , and .

Non-limiting examples of R¹⁶, R¹⁷, and R¹⁸ include: , , , , , , , , , , , , and . Embodiments of Heterocyclic Moiety In certain embodiments, the Heterocyclic Moiety^A or Heterocyclic Moiety^B is of Formula: , , , , , , , , , R⁶ O R¹ _N R⁵ O N HN O , ^R5 , , , , , or . In certain embodiments, the Heterocyclic Moiety^A or Heterocyclic Moiety^B is of Formula: or . In certain embodiments, the Heterocyclic Moiety^A or Heterocyclic Moiety^B is of Formula: , , , , , , 0 , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: O O HN ^N _N O , , ^R5 , , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , , , , , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , , , , , , , , , , , , , , , ,

, , , , or . In certain embodiments, the Heterocyclic Moiety^A or Heterocyclic Moiety^B is of Formula: , , , , , , , , , , , , , , , , , or . In certain embodiments, the Heterocyclic Moiety^A or Heterocyclic Moiety^B is of Formula: , , , , , , , , , , , , , , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , 5 , or . In certain embodiments, the Heterocyclic Moiety^A or Heterocyclic Moiety^B is of Formula: , , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , , , , , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , , , , , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , , , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: R⁶ R⁵ 1, 2, or 3 O N HN O , , , , R⁵ 1, 2, or 3 O N HN O , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , , , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , , or . In certain embodiments, the Heterocyclic Moiety^A is of Formula: , , , or . In certain embodiments, the Heterocyclic Moiety^A or Heterocyclic Moiety^B is of Formula: , , , or . In certain embodiments, the Heterocyclic Moiety^A or Heterocyclic Moiety^B is of Formula: , , or . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from:

and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: H H O N O R¹² O N O R¹² N (R) (R) N N N R⁵ H H H O N O R¹² N (R) N N H and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from:

and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from: and . In certain embodiments the Heterocyclic Moiety^A is selected from:

and . In certain embodiments the Heterocyclic Moiety^A is selected from: H O N O R¹² H O N O R¹² (S) (R) N N H and H . Embodiments of KRAS Targeting Ligand^A and KRAS Targeting Ligand^B In alternative embodiments KRAS Targeting Ligand^A and KRAS Targeting Ligand^B is

or wherein R⁴⁸ is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, - NR⁷R⁸, -OR⁷, or -SR⁷. In certain embodiments R⁴⁸ is hydrogen. In certain embodiments, KRAS Targeting Ligand^A and KRAS Targeting Ligand^B is selected from: and . In certain embodiments, KRAS Targeting Ligand^A and KRAS Targeting Ligand^B is selected from: and . 5 In certain embodiments, KRAS Targeting Ligand^A and KRAS Targeting Ligand^B is selected from: and . In certain embodiments, KRAS Targeting Ligand^A and KRAS Targeting Ligand^B are: . In certain embodiments, KRAS Targeting Ligand^A is selected from: , , , , , and . In certain embodiments, KRAS Targeting Ligand^A is selected from: , , and . In certain embodiments, KRAS Targeting Ligand^A is selected from: , , , , , , , , ,

, , , , , , , , and . In certain embodiments, KRAS Targeting Ligand^A is selected from:

and . In certain embodiments, KRAS Targeting Ligand^A is selected from:

and . In certain embodiments, KRAS Targeting Ligand^A is selected from:

5

and . In certain embodiments, KRAS Targeting Ligand^A is selected from: , ,

and . In certain embodiments, KRAS Targeting Ligand^A is selected from: and . In certain embodiments, KRAS Targeting Ligand^A is selected from:

and . In certain embodiments, KRAS Targeting Ligand^A is selected from: , and . In certain embodiments, KRAS Targeting Ligand^A is selected from: and . Embodiments of R²⁹ In certain embodiments, R²⁹ is selected from the group consisting of:

. Embodiments of R³² In certain embodiments, R³² is selected from ,

. Embodiments of R³³ In certain embodiments, R³³ is selected from:

and . R⁵² and R⁵³, are independently selected at each instance from hydrogen, halogen, cyano, alkyl, haloalkyl, -NR⁷R⁸, -OR⁷, -SR⁷, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, or bicycle; R⁵⁴ and R⁵⁵ are independently selected at each instance from hydrogen, halogen, cyano, alkyl, haloalkyl, -NR⁷R⁸, -OR⁷, -SR⁷, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, and R³. R⁵⁷ is independently selected from hydrogen, alkyl, haloalkyl, arylalkyl, C(O)R⁴, C(O)NR⁷R⁸, and R⁷. In certain embodiments, R³³ is selected from: , , , , , , , , , , , , , , , , , , and . Nonlimiting examples of R³³ include: and . Example Compounds of the Present Invention In certain embodiments, a compound of the present invention is selected from:

F R³³ _N R²⁹ N N H N N O O ^N N H N N N N O O F F N O N R²⁹ O NH N N O N N O N N N N O

F F N O N R²⁹ N N H N N O ^{O N} N N H N N O R³³ O NH N ^F _OH O N N HN N N N N N O F

or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound of the invention is selected from: 5

or a 5 pharmaceutically acceptable salt thereof. In certain embodiments, a compound of the present invention is selected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments KRAS Targeting Ligand^A-Linker- is selected from and . Additional Embodiments of the Present Invention Chirality Embodiments The compounds of the present invention may have multiple stereocenters (e.g., chiral carbon atoms) including for example one or more stereocenters in the E3 ligase binding moiety (for example or ), one or more stereocenters in the linker, and/or at least one stereocenter in the KRAS binding ligand moiety of the molecule. In certain embodiments, the KRAS-degrading compound of the present invention is provided without regard to stereochemistry. In other embodiments, the KRAS-degrading compound may have one or more chiral carbons presented in an enantiomerically enriched (i.e., greater than about 50%, 60%, 70%, 80% or 90% pure) or even substantially pure form (greater than about 95%, 98% or 99% pure) of R and S stereochemistry. In certain aspects, the KRAS-degrading compound has two enantiomerically enriched and/or substantially pure stereocenters. In certain embodiments one stereocenter is in the R configuration and any others present are either enantiomerically enriched or substantially pure. In certain embodiments one stereocenter is in the S configuration and any others present are either enantiomerically enriched or substantially pure. In certain embodiments one stereocenter is in the R configuration and any others present are without regard to stereochemistry, enantiomerically enriched or substantially pure. In certain embodiments one stereocenter is in the S configuration and any others present are without regard to stereochemistry, enantiomerically enriched or substantially pure. In certain embodiments there is one stereocenter in the E3 ligase binding moiety and it is enantiomerically enriched or substantially pure in the R-configuration, as indicated below. In another embodiment there is one stereocenter in the E3 ligase binding moiety and it enantiomerically enriched or substantially pure in the S-configuration, as indicated below. In certain embodiments is , In certain embodiments is , In certain embodiments there is one stereocenter in the linker portion and it is a mixture of R- and S-configuration. In another embodiment there is one stereocenter in the linker portion and it is enantiomerically enriched or substantially pure R-configuration. In another embodiment there is one stereocenter in the linker portion and it is enantiomerically enriched or substantially pure S-configuration. In certain embodiments the linker contains one or more moieties with a chiral center. Non-limiting examples include heterocycle with an enantiomerically enriched or substantially pure stereocenter for example piperidine with a substituent meta- or ortho to the nitrogen or linking in the meta- or ortho- configuration; piperazine with a substituent or linking in the meta- or ortho- configuration; pyrrolidinone with or without a substituent; and pyrrolidine with or without a substituent. Additional non-limiting examples of linker moieties with at least one chiral center include an alkyl with an enantiomerically enriched or substantially pure stereocenter; an alkene with an enantiomerically enriched or substantially pure stereocenter; an alkyne with an enantiomerically enriched or substantially pure stereocenter; a haloalkyl with an enantiomerically enriched or substantially pure stereocenter; an alkoxy with an enantiomerically enriched or substantially pure stereocenter; an aliphatic group with an enantiomerically enriched or substantially pure stereocenter; a heteroaliphatic group with an enantiomerically enriched or substantially pure stereocenter; and a cycloalkyl with an enantiomerically enriched or substantially pure stereocenter In certain embodiments the linker includes or . In certain embodiments the linker includes , , , or . In certain embodiments the linker includes , , , or . In certain embodiments the linker includes . In certain embodiments the linker includes or . In certain embodiments the linker includes or . In certain embodiments the linker includes or . In certain embodiments the linker includes or . In certain embodiments the linker includes or . In certain embodiments the linker includes or . In certain embodiments the linker includes or . In certain embodiments the linker includes or . In certain embodiments the linker includes or . Embodiments of alkyl In certain embodiments “alkyl” is a C₁-C₁₀alkyl, C₁-C₉alkyl, C₁-C₈alkyl, C₁-C₇alkyl, C1-C6alkyl, C1-C5alkyl, C1-C4alkyl, C1-C3alkyl, or C1-C2alkyl. In certain embodiments “alkyl” has one carbon. In certain embodiments “alkyl” has two carbons. In certain embodiments “alkyl” has three carbons. In certain embodiments “alkyl” has four carbons. In certain embodiments “alkyl” has five carbons. In certain embodiments “alkyl” has six carbons. Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl. Additional non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl. Additional non-limiting examples of “alkyl” include: sec-butyl, sec-pentyl, and sec-hexyl. Additional non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl. Additional non-limiting examples of “alkyl” include: neopentyl, 3-pentyl, and active pentyl. Embodiments of cycloalkyl In certain embodiments “cycloalkyl” is a C3-C8cycloalkyl, C3-C7cycloalkyl, C3- C₆cycloalkyl, C₃-C₅cycloalkyl, C₃-C₄cycloalkyl, C₄-C₈cycloalkyl, C₅-C₈cycloalkyl, or C₆- C8cycloalkyl. In certain embodiments “cycloalkyl” has three carbons. In certain embodiments “cycloalkyl” has four carbons. In certain embodiments “cycloalkyl” has five carbons. In certain embodiments “cycloalkyl” has six carbons. In certain embodiments “cycloalkyl” has seven carbons. In certain embodiments “cycloalkyl” has eight carbons. In certain embodiments “cycloalkyl” has nine carbons. In certain embodiments “cycloalkyl” has ten carbons. Non-limiting examples of “cycloalkyl” include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. Embodiments of haloalkyl In certain embodiments “haloalkyl” is a C1-C10haloalkyl, C1-C9haloalkyl, C1- C₈haloalkyl, C₁-C₇haloalkyl, C₁-C₆haloalkyl, C₁-C₅haloalkyl, C₁-C₄haloalkyl, C₁-C₃haloalkyl, and C1-C2haloalkyl. In certain embodiments “haloalkyl” has one carbon. In certain embodiments “haloalkyl” has one carbon and one halogen. In certain embodiments “haloalkyl” has one carbon and two halogens. In certain embodiments “haloalkyl” has one carbon and three halogens. In certain embodiments “haloalkyl” has two carbons. In certain embodiments “haloalkyl” has three carbons. In certain embodiments “haloalkyl” has four carbons. In certain embodiments “haloalkyl” has five carbons. In certain embodiments “haloalkyl” has six carbons. Non-limiting examples of “haloalkyl” include: , , and . Additional non-limiting examples of “haloalkyl” include: , , , , , , , , , , and . Additional non-limiting examples of “haloalkyl” include: , , and . Additional non-limiting examples of “haloalkyl” include: , , and . Embodiments of heterocycle In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms. Non-limiting examples of “heterocycle” include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane. Additional non-limiting examples of “heterocycle” include pyrrolidine, 3-pyrroline, 2- pyrroline, pyrazolidine, and imidazolidine. Additional non-limiting examples of “heterocycle” include tetrahydrofuran, 1,3- dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane. Additional non-limiting examples of “heterocycle” include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine. Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocycle ring Non-limiting examples of “heterocycle” also include: , , , , , , , , , and . Additional non-limiting examples of “heterocycle” include: , , , , , , , and . Additional non-limiting examples of “heterocycle” include: , , , , , , , and . Non-limiting examples of “heterocycle” also include: , , and . Non-limiting examples of “heterocycle” also include: , , , , , , , and . Additional non-limiting examples of “heterocycle” include: , , , , , and . Additional non-limiting examples of “heterocycle” include: , , , , , and . Embodiments of heteroaryl In certain embodiments “heteroaryl” is a 5 membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms. Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole. Additional non-limiting examples of 5 membered “heteroaryl” groups include: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . In certain embodiments “heteroaryl” is a 6 membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl). Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2 nitrogen atoms include: , , , , , , , , , and . In certain embodiments “heteroaryl” is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: , , , , , , and . Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: , , , , , and . Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: , , , , , and . In certain embodiments “heteroaryl” is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: , , , , , and . Embodiments of aryl In certain embodiments aryl is phenyl. In certain embodiments aryl is napthyl. Embodiments of bicycle The term “bicycle” refers to a ring system wherein two rings share at least one atom in common. These rings can be spirocyclic or fused together and each ring is independently selected from carbocycle, heterocycle, aryl, and heteroaryl. Non-limiting examples of bicycle groups include: , , , , , , , and . When the term “bicycle” is used in the context of a bivalent residue such as Linker the attachment points can be on separate rings or on the same ring. In certain embodiments both attachment points are on the same ring. In certain embodiments both attachment points are on different rings. Non-limiting examples of bivalent bicycle groups include: , , , , , , and . Additional non-limiting examples of bivalent bicycle include: , , , , , and . Embodiments of optional substituents In certain embodiments wherein a variable can be optionally substituted it is not substituted. In certain embodiments wherein a variable can be optionally substituted it is substituted with 1 substituent. In certain embodiments wherein a variable can be optionally substituted it is substituted with 2 substituents. In certain embodiments wherein a variable can be optionally substituted it is substituted with 3 substituents. In certain embodiments wherein a variable can be optionally substituted it is substituted with 4 substituents. Embodiments of Aliphatic and Heteroaliphatic In certain embodiments “aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon. In these embodiments aliphatic is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions. In certain embodiments, "aliphatic" is used to indicate those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, mono- unsaturated, di-unsaturated, tri-unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in a cis or trans configuration. In certain embodiments, the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In certain embodiments, the aliphatic group contains from 1 to about 8 carbon atoms In certain embodiments the aliphatic group is C₁-C₂, C₁-C₃, C₁-C₄, C₁- C₅ or C₁-C_6. The specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species. For example, the term C₁-C₆ aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C1-C4 aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. In certain embodiments, the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety. In certain embodiments "heteroaliphatic" refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom. In certain embodiments, the only heteroatom is nitrogen. In certain embodiments, the only heteroatom is oxygen. In certain embodiments, the only heteroatom is sulfur. In certain embodiments “heteroaliphatic" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In certain embodiments, "heteroaliphatic" is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms. In certain embodiments, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc. IV. LINKERS A Linker is included in the compounds of the present invention. Linker is a chemically stable bivalent group that attaches an E3 Ligase binding portion to a KRAS Targeting Ligand. According to the invention, any desired linker, as described herein, can be used as long as the resulting compound has a stable shelf life, for example at least 1 month, 2 months, 3 months, 6 months or 1 year as part of a pharmaceutically acceptable dosage form, and itself is pharmaceutically acceptable. Linker as described herein can be used in either direction, i.e., either the left end is linked to the E3 Ligase binding portion and the right end to the KRAS Targeting Ligand, or the left end is linked to the KRAS Targeting Ligand and the right end is linked to the E3 Ligase binding portion. In certain embodiments Linker is a bond. In certain embodiments, the Linker has a chain of 2 to 14, 15, 16, 17, 18 or 20 or more carbon atoms of which one or more carbons can be replaced by a heteroatom such as O, N, S, or P. In certain embodiments the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous atoms in the chain. For example, the chain may include 1 or more ethylene glycol units that can be contiguous, partially contiguous or non-contiguous (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units). In certain embodiments the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 contiguous chains which can have branches which can be independently alkyl, aryl, heteroaryl, alkenyl, or alkynyl, aliphatic, heteroaliphatic, cycloalkyl or heterocycle substituents. In other embodiments, the linker can include or be comprised of one or more of ethylene glycol, propylene glycol, lactic acid and/or glycolic acid. Lactic acid segments tend to have a longer half-life than glycolic acid segments. Block and random lactic acid-co-glycolic acid moieties, as well as ethylene glycol and propylene glycol, are known in the art to be pharmaceutically acceptable and can be modified or arranged to obtain the desired half-life and hydrophilicity. In certain aspects, these units can be flanked or interspersed with other moieties, such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocycle, cycloalkyl, etc., as desired to achieve the appropriate drug properties. In certain embodiments, Linker is selected from: (LI). In one aspect, Linker is selected from the group consisting of a moiety of Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, Formula LVII Formula LVIII, Formula IX and Formula LX: (LII), (LIII), (LIV), (LV), (LVI), (LVII), (LVIII), (LIX), and (LX); wherein all variables are as defined herein. In certain embodiments, Linker is selected from: . In one aspect, Linker is selected from the group consisting of a moiety of Formula LDI, Formula LDII, Formula LDIII, Formula LDIV, Formula LDV, Formula LDVI, and Formula LDVII: (LDI), (LDII), (LDIII), (LDIV), (LDV), (LDVI), and (LDVII), wherein all variables are described herein. The following are non-limiting examples of Linkers that can be used in this invention. Based on this elaboration, those of skill in the art will understand how to use the full breadth of Linkers that will accomplish the goal of the invention. In certain embodiments Linker is selected from:

In certain embodiments Linker is selected from: O O O _O N N N N

In certain embodiments Linker is selected from:

In certain embodiments Linker is selected from:

In certain embodiments Linker is selected from: N O N OH N and . In certain embodiments Linker is selected from: or . In certain embodiments Linker is selected from: and . Non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, and R²⁴ include:

. Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, and R²⁴ include: . Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, and R²⁴ include: . In additional embodiments, the Linker moiety is an optionally substituted (poly)ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, ethylene glycol units, or optionally substituted alkyl groups interspersed with optionally substituted, O, N, S, P or Si atoms. In certain embodiments, the Linker is flanked, substituted, or interspersed with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. In certain embodiments, the Linker may be asymmetric or symmetrical. In certain embodiments, Linker can be a nonlinear chain, and can be, or include, aliphatic or aromatic or heteroaromatic cyclic moieties. In any of the embodiments of the compounds described herein, the Linker group may be any suitable moiety as described herein. In certain embodiments, the Linker is selected from the group consisting of: and . In certain embodiments, the Linker is selected from the group consisting of: and . In certain embodiments, the Linker is selected from the group consisting of:

5 and . In certain embodiments, the Linker is selected from the group consisting of: 10

and . In certain embodiments, the Linker is selected from the group consisting of:

and . In certain embodiments, the Linker is selected from the group consisting of: and . In certain embodiments, the Linker is selected from the group consisting of: and . In certain embodiments Linker or a portion thereof is selected from: . V. METHODS OF TREATMENT A compound of the present invention or a pharmaceutically acceptable salt thereof can be used in an effective amount to treat a KRAS mediated disorder in a patient, in need thereof. Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for treating cancer in a patient in need thereof; wherein there is a need of KRAS inhibition for the treatment of cancer. In one aspect, a compound of the present invention is used to treat a KRAS mediated cancer, wherein the KRAS has mutated from the wild-type. There are a number of possibilities for KRAS mutations. In some embodiments, the KRAS mutation is a missense mutation encoding a substituted codons. In certain nonlimiting embodiments, the substitution is selected from K5E, K5N, G12A, G12C, G12D, G12E, G12F, G12I, G12L, G12N, G12R, G12S, G12V, G12W, G12Y, G13A, G13C, G13D, G13E, G13I, G13N, G13R, G13S, G13V, V14I, P34L, P34Q, P34R, I36M, T58I, A59S, A59T, G60R, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, R68S, H95D, H95Q, H95R, Y96C, Y96D, V152G, D153V, F156I, F156L, or a combination thereof. In certain embodiments the mutation is a G12D mutation. In certain aspects, the cancer has developed one or more KRAS mutations following treatment with at least one KRAS inhibitor for example, a covalent inhibitor (such as sotorasib or adagrasib). In yet another aspect, the cancer has one or more KRAS mutations or non-KRAS mutations that renders the cancer intrinsically resistant to KRAS inhibitor treatment, for example, a G12V mutation. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to, or has acquired a resistance to, a KRAS inhibitor such as sotorasib or adagrasib. In certain embodiments the compound of the present invention is used to treat a mutant KRAS mediated disorder, wherein KRAS has a mutation encoding a missense substitution at one of the listed codon sites in Table 1. The mutation may, for example, be selected from one of the listed exemplary mutations, or may be a different mutation. In certain embodiments the mutant KRAS mediated disorder has two substitutions selected from the table above. In other embodiments the mutant KRAS mediated disorder has three substitutions selected from the table above. In other embodiments the mutant KRAS mediated disorder has four or more mutations, which may optionally be selected from the table above. In certain embodiments the mutant KRAS mediated disorder has a G12D substitution and one additional substitution which may optionally be selected from the table above. In some of these embodiments the mutant KRAS mediated disorder has a G12D substitution and two additional substitutions that may optionally be selected from the table above. In certain embodiments the mutant KRAS mediated disorder has a G12V substitution and one additional substitution which may optionally be selected from the table above. In some of these embodiments the mutant KRAS mediated disorder has a G12V substitution and two additional substitutions that may optionally be selected from the table above. In certain embodiments a compound of the present invention is more active against a disorder driven by a mutated KRAS than wild-type KRAS. In certain embodiments the KRAS mediated disorder is mutant KRAS mediated cancer. In certain embodiments the KRAS mediated cancer has a substitution selected from K5E, K5N, G12A, G12C, G12D, G12E, G12F, G12I, G12L, G12N, G12R, G12S, G12V, G12W, G12Y, G13A, G13C, G13D, G13E, G13I, G13N, G13R, G13S, G13V, V14I, P34L, P34Q, P34R, I36M, T58I, A59S, A59T, G60R, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, R68S, H95D, H95Q, H95R, Y96C, Y96 bi i n thereof. In certain embodiments a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12D substitution. In certain embodiments, a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12V substitution. In certain embodiments, a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12C substitution. In certain embodiments, a compound of the present invention is used to treat a KRAS mediated cancer wherein the KRAS has a G12R substitution. In certain embodiments, a compound of the present invention is used to treat a cancer that is resistant to at least one KRAS inhibitor, for example a cancer that is resistant to a KRAS inhibitor such as sotorasib and/or adagrasib. In certain embodiments, a compound of the present invention is used to treat a cancer that has acquired resistance to a first generation KRAS inhibitor, for example a cancer that has acquired resistance to a KRAS inhibitor such as sotorasib and/or adagrasib. In certain embodiments, the method comprises administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination or alternation with another bioactive agent or combination of agents, to a patient in need thereof. In other embodiments, the patient is administered an additional therapeutic agent. In other embodiments, the compound as described herein, and the additional therapeutic agent are administered simultaneously or sequentially. In certain embodiments, the patient is a human. As degraders of mutant KRAS, the compounds and compositions of this application are particularly useful for treating or lessening the severity of a disease, condition, or disorder where mutant KRAS is implicated in the disease, condition, or disorder. In one aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where mutant KRAS is implicated in the disease state. Another aspect of the present invention provides a method of treating a proliferative disease. The method comprises administering an effective amount of a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof and optionally a pharmaceutically acceptable carrier to a patient in need thereof. In some embodiments, the disease is mediated by KRAS. In other embodiments, KRAS plays a role in the initiation or development of the disease. In certain embodiments, the disease or disorder is cancer or a proliferation disease. In certain embodiments, the KRAS mediated disorder is an abnormal cell proliferation, including, but not limited to, a solid or hematological cancer. Solid tumors that can be treated with the compounds described herein include, but are not limited to lung cancers, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), breast cancers including inflammatory breast cancer, ER-positive breast cancer including tamoxifen resistant ER-positive breast cancer, and triple negative breast cancer, colon cancers, midline carcinomas, liver cancers, renal cancers, prostate cancers including castrate resistant prostate cancer (CRPC), brain cancers including gliomas, glioblastomas, neuroblastoma, and medulloblastoma including MYC-amplified medulloblastoma, colorectal cancers, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcomas, ependymomas, head and neck cancers, melanomas, squamous cell carcinomas, ovarian cancers, pancreatic cancers including pancreatic ductal adenocarcinomas (PDAC) and pancreatic neuroendocrine tumors (PanNET), osteosarcomas, giant cell tumors of bone, thyroid cancers, bladder cancers, urothelial cancers, vulval cancers, cervical cancers, endometrial cancers, mesotheliomas, esophageal cancers, salivary gland cancers, gastric cancesr, nasopharangeal cancers, buccal cancers, cancers of the mouth, GIST (gastrointestinal stromal tumors), NUT-midline carcinomas, testicular cancers, squamous cell carcinomas, hepatocellular carcinomas (HCC), MYCN driven solid tumors, and NUT midline carcinomas (NMC). In certain embodiments, the disease or disorder is multiple myeloma. In certain embodiments, the hematological cancer is acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), hairy-cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, mixed lineage leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, B cell acute lymphoblastic leukemia, diffuse large B cell lymphoma, Myc and B-Cell Leukemia (BCL)2 and/or BCL6 rearrangements/overexpression [double- and triple- hit lymphoma], myelodysplastic/myeloproliferative neoplasm, mantle cell lymphoma including bortezomib resista l ll l h In certain embodiments, the disease or disorder is sarcoma of the bones, muscles, tendons, cartilage, nerves, fat, or blood vessels. In certain embodiments, the disease or disorder is soft tissue sarcoma, bone sarcoma, or osteosarcoma. In certain embodiments, the disease or disorder is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Karposi's sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, meningiosarcoma, botryoid sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma. In certain embodiments a compound of the present invention or a pharmaceutically acceptable salt thereof is used as a medicament in therapeutic treatment of a patient suffering from cancer, in particular non-small-cell lung cancer, with KRAS activating mutations as determined by next-generation sequencing (NGS), comprising determining the KRAS activating mutations status in said patient and then administering the compound of the present invention, or a pharmaceutically acceptable salt thereof, to said patient. In certain embodiments, said method is used to treat a condition selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immunologically-mediated diseases. In certain embodiments, the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondyiarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, and other arthritic conditions, neuroinflammation, allergy, pain, neuropathic pain, fever, pulmonary disorders, lung inflammation, adult respiratory distress chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, autoimmune disease, graft vs. host reaction and allograft rejections, cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bone cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and/or basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), angiogenesis including neoplasia, metastasis, central nervous system disorders, central nervous system disorders having an inflammatory or apoptotic component, peripheral neuropathy, or B-Cell Lymphoma. This application further embraces the treatment of cell proliferative disorders such as hyperplasias, dysplasias and pre-cancerous lesions. Dysplasia is the earliest form of pre- cancerous lesion recognizable in a biopsy by a pathologist. The compounds may be administered for the purpose of treating said hyperplasias, dysplasias or pre-cancerous lesions. Examples of pre-cancerous lesions may occur in skin, esophageal tissue, breast and cervical intra-epithelial tissue. KRAS and KRAS-mutant associated disorders Mutation of KRAS leads to the accumulation of GTP-bound KRAS and the unrestricted activation of MAP kinase, PI3K-AKT-mTOR, and the tumor invasion and metastasis-inducing protein 1 (TIAM1-RAC) and RAS-related protein (RAL) signaling pathways, and has been implicated in many types of human cancer. KRAS is the most commonly mutated gene in human cancers, present in approximately 14% of all human cancers and contributing to over 200,000 new cancer patients per year in the United States (Parikh et al. Drugging KRAS: current perspectives and state-of-art review. Journal of Hematology & Oncology. 15:152(2022)). Mutations of KRAS cause unrestricted activation of the RAF-MEK-ERK and PI3K-AKT pathways. KRAS The Kirsten rat sarcoma viral oncogene homolog (KRAS) gene (Entrez 3845) encodes the KRAS protein that is a member of the RAS/MAPK pathway signaling pathway. The KRAS gene is a member of the Ras family of oncogenes, which also includes two other genes: HRAS and NRAS. The KRAS protein is a membrane-associated GTPase that converts GTP into GDP. The KRAS protein acts like a molecular switch that is turned on and off by the GTP and GDP molecules, respectively, to control cellular differentiation, growth, and survival. The KRAS protein is turned on (activated) by binding to a molecule of GTP whereby the activated KRAS protein transmits cellular signaling. The KRAS protein is turned off (inactivated) when it converts the GTP to GDP. When the KRAS protein is bound to GDP, it does not transmit cellular signaling. The amino acid positions G12, G13, and Q61 are commonly substituted for different residues by missense mutations, and account for the overwhelming majority of KRAS mutations in cancer. Alternative splicing of KRAS encodes isoforms KRAS4A and KRAS4B, and despite their raw similarity, these isoforms have divergent functions when expressed in non-native tissue types. This hetero i i lik l d diff b ween isoforms in the C- terminal hyper-variable regions. For clinical and research purposes, KRAS refers to the KRAS4B isoform which is the gene product most frequently expressed in human cells (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol. 15:152(2022)). Dysregulated isoform expression and missense mutations at the sequences encoding the hotspot codons G12, G13, and Q61 are thought to be core drivers of cancer. KRAS Pan Targeting KRAS mutations with drugs has been considered extremely challenging for many years, even earning the nickname, “the undruggable gene” (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol. 15:152(2022)). Mutant KRAS is found in 32% of lung cancers, 40% of colorectal cancers, and between >90% of pancreatic cancer cases (Table 2). In fact, KRAS is mutated in 1 in 7 (~14%) of all human cancers (Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med.23(6):703-713(2017 Jun)). An estimated 240,000 new patients per year each harbor a KRAS mutation. The implications of different KRAS mutations for prognosis vary between cancer types, but individual KRAS mutations are demonstrated to associate with poorer outcomes in certain cancers, for example, colorectal cancer, non-small cell lung cancer (NSCLC), and others. Table 2^*. KRAS mutation incidence in different KRAS-associated disorders. KRAS muta G12X (%) Disorder tion G12C G G13X Q61X incidence (%) 12D G12V (%) (%) (%) (%) (%) Pancreatic adenocarcinoma 91 91 1 39 31 2 7 Non-small cell lung 88 cancer 23 41 12 22 5 2 Adenocarcinoma 33 Squamous cell carcinoma 5 Colorectal 65 adenocarcinoma 27.9-43.7 6.5 27.5 20 19 4.5 Cholangiocarcinoma 9.5-18.2 71 5 35 22 5 13 Esophageal carcinoma 4.5-9.1 53 6 25 19 19 <1 Gastric 9. 44 adenocarcinoma 8 <1 26 <1 37 11 ^*Reproduced herein from Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol.15:152(2022). KRAS G12D G12 is the most frequently altered codon found in cancer, accounting for 80% of all KRAS mutations and is found in 12% of all patients (Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 23(6):703-713(2017 Jun)). An estimated 71,200 new patients per year in the United States each harbor a KRAS G12D mutation. The KRAS G12D mutation is the most common KRAS mutation found in pancreatic adenocarcinoma (Table 2). KRAS G12V An estimated 55,100 new patients per year in the United States each harbor a KRAS G12V mutation. The KRAS G12V mutation is the second most common KRAS mutation found in pancreatic adenocarcinoma (Table 2). Pancreatic Cancer KRAS mutation is an early and initiating event of pancreatic cancer. KRAS mutation occurs in 90% of all pancreatic adenocarcinoma patients (Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 23(6):703-713(2017 Jun)). Pancreatic cancer is the deadliest cancer in the United States, as the 5-year survival rate of pancreatic cancer is 8% (Siegel, R.L. et al. Cancer statistics. CA Cancer J Clin.66:7–30(2016)). Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death among cancer patients in the United States and is one of the major causes of morbidity and mortality worldwide (Siegel, R.L. et al. Cancer statistics. CA Cancer J Clin.66:7–30(2016)). Standard of care for PDAC is surgery followed by adjuvant therapy; however, only 15-20% of patients are even eligible for surgery (Waters, A.M. & Der, C.J. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med. 8(9):a031435(2018 Sep)). Therapeutic approaches have been largely unsuccessful in PDAC (Id.). KRAS mutation is a hallmark of PDAC, occurring in greater than 90% of all PDAC patients (Id.) (Table 2). This is supported by in vitro data demonstrating the central role of KRAS in proliferation of PDAC cancer cell models. For example, knockdown of KRAS by RNA interference (RNAi) demonstrates reduced cellular proliferation and induction of apoptosis in several independent human PDAC model cancer cell lines, supporting the central role of KRAS in the development of this cancer (Collisson, E.A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 17(4):500-503(2011 Apr)). Complete ablation of endogenous KRAS in PDAC model cells by CRISPR/Cas-mediated genome editing significantly reduced in vitro proliferation and in vivo tumorigenic growth, further supporting the potential for KRAS targeting agents for the treatment of PDAC ((Muzumdar, M.D. et al. Survival of pancreatic cancer cells lacking KRAS function. Nat. Commun. 8(1):1090(2017)). PDAC development is a step-wise progression lasting an estimated 12 years (Iacobuzio- Donahue, C.A. et al. Genetic basis of pancreas cancer development and progression: Insights from whole-exome and whole-genome sequencing. Clin Cancer Res. 18:4257–4265(2012)), characterized by histologically defined lesions showing increasingly disrupted cellular morphology, nuclear atypia, and dysplastic growth (Cox, A.D. & Der, C.J. Ras history: The saga continues. Small GTPases. 1(1):2-27(2010 Jul)). Activating KRAS mutations are an early, initiating event that induces the transformation of normal pancreatic duct epithelium into pancreatic intraepithelial neoplasms (PanINs). Although infrequent in other forms of cancer, G12R mutations comprise 16% of all KRAS mutations in PDAC (Waters, A.M. & Der, C.J. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med.8(9):a031435(2018 Sep)). In certain aspects an effective amount of a compound of the present invention is used to treat pancreatic cancer. Colorectal Cancer Colorectal cancer is one of the most common cancers worldwide (Porru, M. et al. Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities. J Exp Clin Cancer Res. 37(1):57(2018 Mar 13). Most colorectal cancers are adenocarcinomas. KRAS is mutated in between 27.9-43.7% of all colorectal adenocarcinoma (Table 2). The current standard of care in colorectal cancer is a combination of different chemotherapeutic drugs, comprising either protracted infusion of 5-fluorouracil (5-FU) modulated by leucovorin in combination with irinotecan (FOLFIRI) or with oxaliplatin (FOLFOX), capecitabine and oxaliplatin combination (XELOX), or 5-FU, leucovorin, irinotecan, and oxaliplatin (FOLFOXIRI) (Id.). In certain aspects an effective amount of a compound of the present invention is used to treat colorectal cancer. Lung Cancer Lung cancer is the most common form of cancer and responsible for the most cancer- related deaths worldwide (Westcott, P.M.K. & To, M.D. The genetics and biology of KRAS in lung cancer. Chin J Cancer. 32(2):63-70(2013 Feb)). Smoking is the most common risk factor for lung cancer, with an estimated 80% of all lung cancer patients having previously smoked (Id.). KRAS is more frequently mutated in smokers compared to non-smokers, with G12C the most common KRAS mutation in smokers (44%), followed by G12V (19%) (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol.15:152(2022)). In contrast, KRAS G12D is the most frequent KRAS mutation (56%) in non-smokers (Id.). In some embodiments, the lung cancer comprises non-small cell lung cancer (NSCLC). The makeup of KRAS mutation in lung cancer is heterogeneous compared to other KRAS- associated disorders. KRAS is mutated in 23% of all NSCLC (Table 2). The KRAS G12C mutation is the major KRAS mutation in NSCLC, comprising approximately 41% of all KRAS mutations in this population (Table 2) (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol.15:152(2022)). KRAS mutations mostly occur in lung adenocarcinomas, the most common histological subclass of NSCLC. The KRAS G12C mutation is the major KRAS mutation in lung adenocarcinoma, comprising approximately 43% of all KRAS mutations in this population (Waters, A.M. & Der, C.J. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med. 8(9):a031435(2018 Sep)). The frequency of KRAS mutation is lower in squamous cell carcinoma (another subclass of NSCLC), comprising 5% of all cases (Table 2) (Id.). In some embodiments, the NSCLC comprises lung adenocarcinoma or squamous cell carcinoma. In certain aspects an effective amount of a compound of the present invention is used to treat lung cancer. VI. COMBINATION THERAPY A compound described herein or a pharmaceutically acceptable salt thereof can be used in an effective amount alone or in combination with another bioactive agent or second therapeutic agent to treat a human patient with a KRAS mediated disorder. The term “bioactive agent” is used to describe an agent, other than the selected compound according to the present invention, which can be used in combination or alternation with a compound of the present invention to achieve a desired result of therapy. In certain embodiments, the compound of the present invention and the bioactive agent are administered in a manner that th i i i d i l i i i d , for example, have time- period overlapping Cmax, Tmax, AUC or another pharmacokinetic parameter. In another embodiment, the compound of the present invention and the bioactive agent are administered to a patient in need thereof that do not have overlapping pharmacokinetic parameter, however, one has a therapeutic impact on the therapeutic efficacy of the other. MAPK Inhibitors In certain embodiments, the bioactive agent is an inhibitor of a protein involved in signaling through the mitogen-associated protein kinase (MAPK) pathway. Proteins involved in MAPK signaling include but are not limited to EGFR, SOS (including but not limited to SOS1), RAS (including but not limited to KRAS, NRAS, and HRAS), SHP2, RAF (including but not limited to BRAF), MEK (including but not limited to MEK1 and MEK2) and ERK. EGFR In certain embodiments, the bioactive agent is an epidermal growth factor receptor (EGFR) inhibitor, including, for example gefitinib (Iressa), erlotinib (Tarceva), lapatinib (Tykerb), osimertinib (Tagrisso), neratinib (Nerlynx), vandetanib (Caprelsa), dacomitinib (Vizimpro), rociletinib (Xegafri), afatinib (Glotriff, Giotriff, Afanix), lazertinib, or nazartib. Additional examples of EGFR inhibitors include rociletinib (CO-1686), olmutinib (Olita), naquotinib (ASP8273), nazartinib (EGF816), PF-06747775, icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, dacomitinib (PF-00299804; Pfizer), brigatinib (Alunbrig), lorlatinib, and PF-06747775 (PF7775). In certain embodiments, the bioactive agent is a first-generation EGFR inhibitor such as erlotinib, gefitinib, or lapatinib. In certain embodiments, the bioactive agent is a second- generation EGFR inhibitor such as afatinib and/or dacomitinib. In certain embodiments, the bioactive agent is a third-generation EGFR inhibitor such as osimertinib. In certain embodiments a compound of the present invention is administered to a patient in need thereof in combination with an anti-EGFR antibody, for example, cetuximab, panitumab, or necitumab. In certain embodiments a compound of the present invention is administered to a patient in need thereof in combination with cetuximab. In certain embodiments a compound of the present invention is administered to a patient in need thereof in c bi i i h i b In certain embodiments a compound of the present invention is administered to a patient in need thereof in combination with necitumab. SOS In certain embodiments, the bioactive agent is a son of sevenless (SOS) inhibitor. In certain embodiments, the bioactive agent is a SOS1 inhibitor, including but not limited to BI-1701963, RGT-018, MRTX-0902, BAY-293, BI-3406, SOS1-IN-9, RAS In certain embodiments, the bioactive agent is a rat sarcoma virus (RAS) protein inhibitor. Examples of RAS inhibitors include but are not limited to rigosertib, RMC-6236, Reolysin and siG12D LODER. In certain embodiments, the bioactive agent is an additional KRAS inhibitor. Nonlimiting examples of KRAS inhibitors include sotorasib, adagradib, JDQ443, D-1553, mRNA-5671, JAB-21822, IBI351, GFH925, LY3537982, ELI-002, ASP3082, RMC-6291, ERAS-3490, IMM-1-104, and GDC-6036. In certain embodiments, the bioactive agent is an NRAS inhibitor. In certain embodiments, the bioactive agent is an HRAS inhibitor. SHP2 In certain embodiments, the bioactive agent is a Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) inhibitor. Examples of SHP2 inhibitors include but are not limited to BBP-398, SHP099, PF-07284892 (ARRY-558), RG6433, JAB-3068, JAB-3312, ERAS-601, HBI-2376, SH3809, ET0038, BPI-442096, TNO155, RMC-4630, RMC-4550, and RLY-1971. Additional SHP-2 inhibitors can be found in U.S. Patent No.11,634,417. RAF In certain embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, Vemurafinib (N-[3-[[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3- yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3- (trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide;4- methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo- 3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(1-methyl-6- (pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3- (trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H- imidazol-2-yl]pyridi l ( ifl h l) h l b i idazol-2-amine), 2- Bromoaldisine (2-Bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf Kinase Inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), Sorafenib N- Oxide (4-[4-[[[[4-Chloro-3(trifluoroMethyl)phenyl]aMino]carbonyl]aMino]phenoxy]-N- Methyl-2pyridinecarboxaMide 1-Oxide), PLX-4720, vemurafenib, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (Encorafenib). In certain embodiments, the bioactive agent is a dual RAF/MEK inhibitor such as Avutometinib (RO5126766, CH5126766, VS-6766, CKI-27, R-7304, RG-7304). MEK In certain embodiments, the bioactive agent is a Mitogen-activated protein kinase kinase (MEK, MAP2K, MAPKK) inhibitor. MEK inhibitors are well known, and include, for example, trametinib/GSKl120212 (N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8- dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3- methylbenzimidazole-5-carboxamide), pimasertib/AS703026/MSC 1935369 ((S)-N-(2,3- dihydroxypropyl)-3-((2-fluoro-4- iodophenyl)amino)isonicotinamide), XL-518/GDC-0973 (l- ({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol), refametinib/BAY869766/RDEAl 19 (N-(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]- benzamide), TAK733 ((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)- 8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162/ARRY438162 (5-[(4-Bromo-2- fluorophenyl)amino]-4-fluoro-N-(2- hydroxyethoxy)-1-methyl-1H-benzimidazole-6- carboxamide), R05126766 (3-[[3-Fluoro-2- (methylsulfamoylamino)-4-pyridyl]methyl]-4- methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655/CH4987655 (3,4-difluoro- 2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-l,2-oxazinan- 2yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2 hydroxyethoxy)- 1,5-dimethyl-6-oxo-l,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088. ERK In certain embodiments, the bioactive agent is an extracellular signal-regulated kinase (ERK) inhibitor, including ERK1 and ERK2 inhibitors. Nonlimiting examples of ERK inhibitors include Ulixertinib (BVD-523, VRT752271), VX-11e (4-(2-((2-chloro-4-fluorophenyl)amino)- 5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide), AZD0364, MK-8353 (SCH900353), LY3214996, CC-9003, BIX-02189, SCH772984, ASN007, MRTX-1257, ERK5-IN-2, AZD0364 (ATG-017), FR180204, . Immunotherapeutics In one aspect of this embodiment, the bioactive agent is an immune modulator, including but not limited to a checkpoint inhibitor, including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V- domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecule, peptide, nucleotide, or other inhibitor. In certain aspects, the immune modulator is an antibody, such as a monoclonal antibody. PD-1 inhibitors that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibit immune suppression include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF- 06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1/VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression, include for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibits immune suppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884 and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol- Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro). In certain embodiments, the PD-L1 inhibitor is a small molecule PD-L1 inhibitor including but not limited to INCB99280, BMS-202, BMS-1001, BMS-1166, CA-170, TPP-1, AUNP-12, and DPPA-1. In certain embodiments the checkpoint inhibitor is selected from nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®; and pidilizumab/CT-011, MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559, a PDL2/lg fusion protein such as AMP 224 or an inhibitor of B7- H3 (e.g., MGA271 ), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1 , CHK2, A2aR, B-7 family ligands, or a combination thereof. In another embodiment, one of the active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the female reproductive system such as breast, ovarian, endometrial, or uterine cancer, in combination or alternation with an effective amount of an estrogen inhibitor including, but not limited to, a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist or agonist. Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth. In contrast, fulvestrant, a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors. Non-limiting examples of anti-estrogen compounds are provided in WO201419176 assigned to Astra Zeneca, WO2013090921, WO 2014203129, WO2014203132, and US2013/0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703, 810, as well as US20150005286, WO2014205136, and WO2014205138. Additional non-limiting examples of anti-estrogen compounds include: SERMS such as anordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestratnt; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone. Other estrogenic ligands that can be used according to the present invention are described in U.S. Patent Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO2011/156518, US Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos. 9,078,871; 8,853,423; 8,703,810; US 2015/0005286; and WO 2014/205138, US2016/0175289, US2015/0258080, WO2014191726, WO2012084711; WO2002013802; WO2002004418; WO2002003992; WO2002003991; WO2002003990; 3986; WO2002003977; WO2002003976; WO2002003975; WO2006078834; US 6821989; US 2002/0128276; US 6777424; US 2002/0016340; US 6326392; US 6756401; US 2002/0013327; US 6512002; US 6632834; US 2001/0056099; US 6583170; US 6479535; WO1999024027; US 6005102; EP 0802184; US 5998402; US 5780497, US 5880137, WO2012048058 and WO2007087684. In another embodiment, active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the male reproductive system such as prostate or testicular cancer, in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor including, but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In certain embodiments, the prostate or testicular cancer is androgen-resistant. Non-limiting examples of anti-androgen compounds are provided in WO 2011/156518 and US Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine. In certain embodiments, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include but are not limited to Crizotinib, Alectinib, ceritinib, TAE684 (NVP- TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113. In certain embodiments, the bioactive agent is an HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab. In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab, tositumomab, and ocrelizumab. In certain embodiments, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib. In certain embodiments, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1- en-1-yl]methyl]piperazin-l-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4- yl)methyl]amino]phenyl]sulfonyl]-2-[(lH- pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT- 737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4- [[(2R)-4-(dimethylamino)- 1-phenylsulfanylbutan-2-yl] amino]-3- nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l, l'-biphenyl]-2-yl)methyl)piperazin-1- yl)-N-((4-((4-morph li ( h l hi )b l) i ) 3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax mesylate, (2Z)- 2-[(5Z)-5-[(3,5- dimethyl-lH-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole; methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9- dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), pogosin, ethyl 2-amino-6-bromo-4-(1- cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, Nilotinib-d3, TW-37 (N-[4-[[2-(1,1- Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1- methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, or G3139 (Oblimersen). In certain embodiments, the bioactive agent is a kinase inhibitor. In certain embodiments, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof. Examples of PI3 kinase inhibitors include, but are not limited to, Wortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib , Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2-[4-[2-(2- Isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9- yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)- methylphosphonate; or Methyl(oxo) {[(2R)-l-phenoxy-2-butanyl]oxy}phosphonium)), BYL- 719 ((2S)-N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2- pyrrolidinedicarboxamide), GSK2126458 (2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4- pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7- Methyl-2-(morpholin-4-yl)-9-(l-phenylaminoethyl)-pyrido[l,2-a]-pyrimidin-4-one), GSK2636771 (2-Methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-lH- benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((l-(7-methyl-2- morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR- 1202/RP5264, GS-9820 ((S)- l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan- 1 -one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4- one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5- dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4 methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[l,2- c]quinaz), AS 252424 (5-[l-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]- thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-N- tert-butylpyridine-3-sulfonamide), Buparlisib (5-[2,6-Di(4-morpholinyl)-4- pyrimidinyl]-4- (trifluoromethyl)-2 idi i ) ( (l d l l) 6-[[4-(methylsulfonyl)-l- piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2- aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6 yl)methyl)piperazin-l- yl)-2-hydroxypropan-l-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14- (carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4- oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecan-18- oate), PF-05212384 (N-[4-[[4-(Dimethylamino)-1- piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di- 4-morpholinyl-l,3,5-triazin-2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2-Methyl-2- {4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l- yl]phenyl}propanenitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9- (methoxymethyl)-9a,11a-dimethyl-l,4,7-trioxo-2,3,3a,9,10,ll-hexahydroindeno [4,5h]isochromen- 10-yl] acetate (also known as sonolisib)), LY294002, AZD8186, PF- 4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3- methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422). Examples of BTK inhibitors include ibrutinib (also known as PCI-32765)(Imbruvica™)(1- [(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2- en-1-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292 (N-(3-((5- fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011/0117073, incorporated herein in its entirety), Dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2- methylpyrimidin-4-ylamino)thiazole-5-carboxamide], LFM-A13 (alpha-cyano-beta-hydroxy- beta-methyl-N-(2,5-ibromophenyl) propenamide), GDC-0834 ([R-N-(3-(6-(4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)- 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide], CGI-560 4-(tert-butyl)-N-(3-(8- (phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2- methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin- 2-yl)phenyl)benzamide), CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin- 2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056 (7-benzyl-1-(3-(piperidin-1-yl)propyl)- 2-(4-(pyridin-4-yl) h l) i id i li ( ) ) GDC-0834 ((R)-N-(3-(6- ((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2- yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N- (3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol- 2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4- yl)benzo[h][1,6]naphthyridin-2(1H)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2- hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6- dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), and other molecules capable of inhibiting BTK activity, for example those BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology & Oncology, 2013, 6:59, the entirety of which is incorporated herein by reference. Syk inhibitors include, but are not limited to, Cerdulatinib (4-(cyclopropylamino)-2-((4- (4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6- (1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6- ({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3- dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)- 2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)- pyridazine-3-carboxylic acid amide), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N- (4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine- 5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4- amine), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5- carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2- aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5- fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348 (3-Ethyl-4-methylpyridine), R406 (6- ((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol (3-Hydroxyresveratol), YM193306 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery and Development f l i i ( ) hibi d. Chem.2012, 55, 3614- 3643 incorporated in its entirety herein), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), luteolin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), myricetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein). In certain embodiments, the bioactive agent is a c-MET inhibitor, for example, crizotinib (Xalkori, Crizonix), tepotinib (XL880, EXEL-2880, GSK1363089, GSK089), or tivantinib (ARQ197). In certain embodiments, the bioactive agent is an AKT inhibitor, including, but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine, a FLT-3 inhibitor, including, but not limited to, P406, Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, and KW-2449, or a combination thereof. In certain embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus. In certain embodiments, the bioactive agent is an HSP inhibitor. HSP inhibitors include but are not limited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol. Additional bioactive compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ- 197, MK-0457, M -3 inhibitor, a VKRAS inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a focal adhesion kinase inhibitor, a Map kinase kinase (MEK) inhibitor, a VEGF trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, of atumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5Ą- deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD- 6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3- d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6- mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS- 310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP- 23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof. In certain embodiments the compound is administered in combination with ifosfamide. In certain embodiments, the bioactive agent is selected from, but are not limited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®), trastuzumab-DM1, Pertuzumab (PerjetaTM), Lapatinib (Tykerb®), Gefitinib (Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin (Panretin®), Tretinoin (Vesanoid®), Carfilizomib (KyprolisTM), Pralatrexate (Folotyn®), Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), and Cabozantinib (CometriqTM). In certain aspects, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic, an additional therapeutic agent, or an immunosuppressive agent. Suitable chemotherapeutic bioactive agents include, but are not limited to, a radioactive molecule, a toxin, l f d i i hi h includes any agent that is detrimental to the viability of cells, and liposomes or other vesicles containing chemotherapeutic compounds. General anticancer pharmaceutical agents include: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®), Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L- asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP- 16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™). Examples of additional suitable chemotherapeutic agents include, but are not limited to 1- dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, an alkylating agent, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracycline, an antibiotic, an antimetabolite, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), Chlorambucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens, Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, cytochalasin B, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin (formerly actinomycin), daunirubicin HCL, daunorucbicin citrate, denileukin diftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione, Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coli L-asparaginase, emetine, epoetin-α, Erwinia L- asparaginase, esterified estrogens, estradiol, estramustine phosphate sodium, ethidium bromide, ethinyl estradiol, etidronate, etoposide citrororum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea, idarubicin HCL, ifosfamide, interferon α-2b, irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine, lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL, mercaptipurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL, plimycin, polifeprosan 20 with carmustine implant, porfimer sodium, procaine, procarbazine HCL, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate. In some embodiments, the compound of the present invention is administered in combination with a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1 ); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Inti. Ed Engl.33:183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino- doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such a i i h li id l i livomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5- FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE®, cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, IL), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-1 1 ); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the compound of the present invention. Suitable dosing regimens of combination chemotherapies are known in the ar. For example combination dosing regimes are described in Saltz et al., Proc. Am. Soc. Clin. Oncol.18:233a (1999) and Douillard et al., Lancet 355(9209): 1041 -1047 (2000). Additional therapeutic agents that can be administered in combination with a Compound disclosed herein c i l d b i b i ib f ib hoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), amebaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B). In certain embodiments, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs may “coat” the cancer cell surface, triggering its destruction by the immune system. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor’s microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels. MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells. In one aspect of the present invention, the bioactive agent is an immunosuppressive agent. The immunosuppressive agent can be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a S1P receptor modulator, e.g. fingolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15- deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA4lg (Abatacept), belatacept, LFA3l ( ld b l b ) adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®), Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab, Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen. In some embodiments, the bioactive agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®). In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti- cancer response, or antagonizes an antigen important for cancer. Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-l- 131 ); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab); LUCENTIS® (ranibizumab); SOURIS® (eculizumab); CIMZIA® (certolizumab pegol); SIMPONI® (golimumab); ILARIS® (canakinumab); STELARA® (ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX® (motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); YERVOY® (ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA® (pertuzumab); KADCYLA® (ado- trastuzumab emtansine); and GAZYVA® (obinutuzumab). Also included are antibody- drug conjugates. The combination therapy may include a therapeutic agent which is a non-drug treatment. For example, the compound could be administered in addition to radiation therapy, cryotherapy, hyperthermia, and/or surgical excision of tumor tissue. In certain embodiments the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before o f h d h i In certain embodiments the second therapeutic agent is administered on a different dosage schedule than the compound of the present invention. For example the second therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In another embodiment the first therapeutic agent has a treatment holiday. For example the first therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In certain embodiments both the first and second therapeutic have a treatment holiday. VII. PHARMACEUTICAL COMPOSITIONS A compound of the present invention or a pharmaceutically acceptable salt thereof can be used as a therapeutically active substance, e.g. in the form of a pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. In other embodiments the compound is administered paternally, for example by intravaneous administration. In other embodiments the pharmaceutical composition is administered rectally, e.g. in the form of suppositories. A compound of the present invention or a pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations can, moreover, contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. Medicaments containing a compound of the present invention or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also provided by the present invention, as is a pr f h i d i hi h i b i i g one or more compounds of the present invention and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers. The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of the present invention or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated. In certain embodiments the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms with at least 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt. In some embodiments, compounds disclosed herein or used as described are administered once a day (QD), twice a day (BID), or three times a day (TID). In some embodiments, compounds disclosed herein or used as described are administered at least once a day for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, or longer. In certain embodiments the compound of the present invention is administered once a day, twice a day, three times a day, or four times a day. In certain embodiments the compound of the present invention is administered orally once a day. In certain embodiments the compound of the present invention is administered orally twice a day. In certain embodiments the compound of the present invention is administered orally three times a day. In certain embodiments the compound of the present invention is administered orally four times a day. In certain embodiments the compound of the present invention is administered intravenously once a day. In certain embodiments the compound of the present invention is administered intravenously twice a day. In certain embodiments the compound of the present invention is administered intravenously three times a day. In certain embodiments the compound of the present invention is administered intravenously four times a day. In some embodiments the compound of the present invention is administered with a treatment holiday in between treatment cycles. For example the compound may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In some embodiments a loading dose is administered to begin treatment. For example, the compound may be administered about 1.5x, about 2x, about 2.5x, about 3x, about 3.5x, about 4x, about 4.5x, about 5x, about 5.5x, about 6x, about 6.5x, about 7x, about 7.5x, about 8x, about 8.5x, about 9x, about 9.5x, or about 10x higher dose on the first day of treatment than the remaining days of treatment in the treatment cycle. Additional exemplary loading doses include about 1.5x, about 2x, about 2.5x, about 3x, about 3.5x, about 4x, about 4.5x, about 5x, about 5.5x, about 6x, about 6.5x, about 7x, about 7.5x, about 8x, about 8.5x, about 9x, about 9.5x, or about 10x higher dose on the first 2, 3, 4, 5, 6, 7, 8, 9, or 10 days of treatment than the remaining days of treatment in the treatment cycle. The pharmaceutical composition may also include a molar ratio of the active compound and an additional active agent. For example the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or from about 1.5:1 to about 4:1 of an anti- inflammatory or immunosuppressing agent. These compositions can contain any amount of active compound that achieves the desired result, for example between 0.1 and 99 weight % (wt. %) of the compound and usually at least about 5 wt. % of the compound. Some embodiments contain from about 25 wt. % to about 50 wt. % or from about 5 wt. % to about 75 wt. % of the compound. A pharmaceutically or therapeutically effective amount of the composition will be delivered to the patient. The precise effective amount will vary from patient to patient, and will depend upon the species, age, the subject’s size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. The effective amount for a given situation can be determined by routine experimentation. For purposes of the disclosure, a therapeutic amount may for example be in the range of about 0.01 mg/kg to about 250 mg/kg body weight, more typically about 0. /k b /k i l d se. The subject can be administered as many doses as is required to reduce and/or alleviate the signs, symptoms, or causes of the disorder in question, or bring about any other desired alteration of a biological system. When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. In certain embodiments the dose ranges from about 0.01-100 mg/kg of patient bodyweight, for example about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg. The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. In certain embodiments the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Thus, the composition of the disclosure can be administered as a pharmaceutical formulation includi i bl f l (i l di b l d ub-lingual), rectal, nasal, topical, transdermal, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous), injections, inhalation or spray, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, or by other means of administration containing conventional pharmaceutically acceptable carriers. A typical manner of administration is oral, topical or intravenous, using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrup, suspensions, creams, ointments, lotions, paste, gel, spray, aerosol, foam, or oil, injection or infusion solution, a transdermal patch, a subcutaneous patch, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. The compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like. Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Classes of carriers include, but are not limited to adjuvants, binders, buffering agents, coloring agents, diluents, disintegrants, excipients, emulsifiers, flavorants, gels, glidents, lubricants, preservatives, stabilizers, surfactants, solubilizer, tableting agents, wetting agents or solidifying material. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the p i i Some excipients include, but are not limited, to liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like. The compound can be provided, for example, in the form of a solid, a liquid, spray dried material, a microparticle, nanoparticle, controlled release system, etc., as desired according to the goal of the therapy. Suitable excipients for non-liquid formulations are also known to those of skill in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990). Additionally, auxiliary substances, such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, can be present in such vehicles. A biological buffer can be any solution which is pharmacologically acceptable, and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range. Examples of buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like. For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington’s Pharmaceutical Sciences, referenced above. In yet another embodiment provided is the use of permeation enhancer excipients including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan- thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates). In certain embodiments the excipient is selected from butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxy l h l ll l l i rate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. The pharmaceutical compositions/combinations can be formulated for oral administration. For oral administration, the composition will generally take the form of a tablet, capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are typical oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. Typically, the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. When liquid suspensions are used, the active agent can be combined with any oral, non- toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents can be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like. For ocular delivery, the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcorneal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device. Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid f i bl f l bili i i i liquid prior to injection, or as emulsions. Typically, sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents. The sterile injectable formulation can also be a sterile injectable solution or a suspension in a acceptably nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media. In addition, parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained. Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Administration via certain parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system. A formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration. Preparations according to the disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use. Sterile injectable solutions are prepared by incorporating one or more of the compounds of the disclosure in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, typical m h d f i d i d f -drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Thus, for example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized. Alternatively, the pharmaceutical compositions of the disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of the disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents. Formulations for buccal administration include tablets, lozenges, gels and the like. Alternatively, buccal administration can be effected using a transmucosal delivery system as known to those skilled in the art. The compounds of the disclosure can also be delivered through the skin or muscosal tissue using conventional transdermal drug delivery systems, i.e., transdermal “patches” wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the body surface. In such a structure, the drug composition is typically contained in a layer, or “reservoir,” underlying an upper backing layer. The laminated device can contain a single reservoir, or it can contain multiple reservoirs. In certain embodiments, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single/-multiple dose dry powder inhalers (DPI). The devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung. In certain embodiments an oral formulation is provided. VIII. PHARMACOLOGICAL TESTS The compounds of the present invention and their pharmaceutically acceptable salts possess valuable pharmacological properties. The compounds were investigated in accordance with the test given hereinafter. Genetic Tests for KRAS Mutation Status In some aspects, a compound as described herein, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, is used as a medicament in therapeutic and/or prophylactic treatment of a patient with KRAS activating mutations as determined with a test selected from Agilent Resolution ctDx FIRST assay, cobas KRAS Mutation Test, FoundationOne CDx, Guardant360 CDx, ONCO/Reveal Dx Lung & Colon Cancer Assay (O/RDx-LCCA), therascreen KRAS RGQ PCR Kit, Praxis Extended RAS Panel, or a combination thereof, suffering from cancer, comprising determining the KRAS mutation status in said patient and then administering the compound, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition to said patient. IX. SYNTHETIC METHODS A compound of the present invention may contain one or more asymmetric centers and can therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within this invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the com d b d h h i di id l ntiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. In the embodiments, where optically pure enantiomers are provided, optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound. Chirally pure or chirally enriched compounds may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate. The preparation of compounds of the present invention is further described in more detail in the scheme below. Isolation and purification of the compounds Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick- layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of the present invention can be separated using chiral HPLC. Racemic mixtures of chiral synthetic intermediates may also be separated using chiral HPLC. Salts of compounds of the present invention In cases where a compound of the present invention is basic it may be converted to a corresponding acid addition salt. The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. A specific salt is the f i ll h f b i di l d i inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent. The temperature is maintained between 0 °C and 50 °C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent. Insofar as their preparation is not described in the examples, the compounds the present invention as well as all intermediate products can be prepared according to analogous methods or according to the methods set forth herein. Starting materials are commercially available, known in the art or can be prepared by methods known in the art or in analogy thereto.

X. GENERAL SYNTHESIS Non-limiting distinct methods for preparing compounds of the present invention include those provided in Schemes 1-4. As illustrated in these Schemes and the Examples below, compounds for use in the present invention can be synthesized by one skilled in the art using a range of different retrosynthetic paths. Scheme 1 As shown in Scheme 1, compounds for use in the present invention can be prepared by chemically combining a Heterocyclic Moiety and a Linker followed by subsequent addition of a Targeting Ligand. In certain aspects the Heterocyclic Moiety, Linker, or Targeting Ligand of Scheme 1 is a precursor intermediate that is then fully functionalized later in the synthesis. For example, where Targeting Ligand is the skilled artisan may choose to use it in a protected form and then remove the protecting groups after preparing a protected compound of the present invention (see for example Scheme 1-a).

Scheme 1-a Similarly, one or more moieties of Linker may be installed on the KRAS Targeting Ligand before the molecule is fully assembled or even before the KRAS Targeting Ligand portion of the molecule is fully assembled (see for example Scheme 1-b). Scheme 1-b

In certain aspects protecting group strategies and splitting the linker into multiple moieties are both used to prepare compounds of the present invention (see for example Scheme 1-c). Scheme 1-c

Scheme 2 In the alternative, in Scheme 2 compounds for use in the present invention are prepared by chemically combining a Targeting Ligand and Linker first, followed by subsequent addition of a Heterocyclic Moiety. Like Scheme 1, this process can be accomplished with the use of protecting groups and/or adding Linker portion wise if desired. Additionally, in certain aspects Linker or a portion of Linker is installed on the Targeting Ligand before the Targeting Ligand is completed. For example in Scheme 2-a a linker is installed on the bicyclic Targeting Ligand core in advance of installation of the R³³ and R²⁹ groups. Scheme 2-a

O O Linker Linker ^N _N N _N N H N H Heterocyclic Moiety N N N N N N OH O N O N Cl N F N F F Scheme 3 Heterocyclic LG Linker PG Heterocyclic Moiety Moi Linker PG S_{tep 1} ety ^{Step 2} Heterocyclic _LG Linker Targeting Ligand Moiety Linker Step 3 Heterocyclic Targeting Ligand M^{oiety Linker} In Scheme 3, in Step 1, a nucleophilic Heterocyclic Moiety displaces a leaving group on the Linker to make a Heterocyclic Moiety Linker fragment. In Step 2, the protecting group is removed by methods known in the art to free a nucleophilic site on the linker. In Step 3, the nucleophilic Heterocyclic Moiety Linker fragment displaces a leaving group on the Targeting Ligand to form a compound for use in the present invention. In an alternative embodiment Step 1 and/or Step 2 is accomplished by a coupling reaction instead of a nucleophilic attack. Scheme 4 In Scheme 4, in Step 1, a nucleophilic Targeting Ligand displaces a leaving group on the Linker to make a Targeting Ligand Linker fragment. In Step 2, the protecting group is removed by methods known in the art to free a nucleophilic site on the linker. In Step 3, the nucleophilic Targeting Ligand Linker fragment displaces a leaving group on the Heterocyclic Moiety to form a compound for use in the present invention. In an alternative embodiment Step 1 and/or Step 2 is accomplished by a coupling reaction instead of a nucleophilic attack. XI. EXPERIMENTAL PROCEDURES Abbreviations ABPR Automated back pressure regulator AcCl Acetyl Chloride ACN Acetonitrile AIBN Azobisisobutyronitrile AlCl3 Aluminum trichloride Ag₂CO₃ Silver carbonate Aq. aqueous A_cOH Acetic acid B_Br3 tribromoborane B₂pin₂ Bis(pinacolato)diboron BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl B_nBr Benzyl bromide Boc₂O Di-tert-butyl dicarbonate B_r2 Bromine gas C_lCOOEt Ethyl chloroformate C_AN Ceric ammonium nitrate CDI Carbonyldiimidazole CuI Cuprous iodide CCl₄ Carbon tetrachloride CoCl2 Cobalt (II) chloride CO Carbon monoxide CO2 Carbon dioxide COMU (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino- morpholino-carbenium hexafluorophosphate Cu copper CH3CN Acetonitrile CHCl₃ Chloroform; trichloromethane CH2Cl2, DCM Methylene chloride; dichloromethane Cs2CO3 Cesium carbonate CsF Cesium fluoride DAST Diethylaminosulfur trifluoride DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE Dichloroethane; ethylene chloride DIAD Diisopropyl azodicarboxylate DIEA, DIPEA N,N-diisopropylethylamine DMA; DMAc N,N-dimethylacetamide DMAP 4-Dimethylaminopyridine DMF N,N-dimethylformamide DMSO Dimethylsulfoxide DPPP 1,3-Bis(diphenylphosphino)propane EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Et3SiH Triethylsilane EtOAc; EA Ethyl acetate EtOH Ethanol FeBr₃ Iron (III) bromide HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate HCl Hydrochloric acid HCOONH₄ Ammonium formate H₂ hydrogen gas H_2O Water H_2O2 Hydrogen peroxide H_COOH Formic acid H_3PO2 Hypophosphorous acid H_2SO4 Sulfuric acid H_OBt hydroxybenzotriazole I_nCl3 ^{Indium(III) chloride} I_PA ^{Isopropyl alcohol} K_HCO3 ^{Potassium bicarbonate} K_OAc ^{Potassium acetate} K_OH ^{Potassium hydroxide} K_O ^t _Bu ^{Potassium tert-butoxide} K_2CO3 Potassium carbonate K_HSO4 ^{Potassium bisulfate} K_I Potassium iodide K_OCN ^{Potassium cyanate} K_MnO4 Potassium permanganate K_3PO4 Tribasic potassium phosphate K_SCN ^{Potassium thiocyanate} L_ac ^{Lactic acid} L_CMS Liquid chromatography–mass spectrometry L_iAlH4 ^{Lithium aluminum hydride} _LiHMDS Lithium bis(trimethylsilyl)amide _LiOH ^{Lithium hydroxide} _LDA Lithium diisopropylamide _Me Methyl _MeCN acetonitrile _MeI ^{Methyl iodide} _MeOH ^Methanol _MnO2 Manganese dioxide _MgCl2 Magnesium chloride MgSO₄ Magnesium sulfate _MsCl Methanesulfonylchloride _MTBE Methyl tert-butyl ether NH4OAc Ammonium acetate N2 Nitrogen gas NaCN Sodium cyanide NH₄Cl Ammonium chloride NH₄OH Ammonium hydroxide NH₂OH Hydroxylamine NaBH(OAc)₃ Sodium triacetoxyborohydride NaBH4 Sodium borohydride NaClO2 Sodium chlorite Na2SO4 Sodium sulfate NaSMe Sodium methanethiolate Na₂S₂O₃ Sodium thiosulfate NaH Sodium hydride NaOH Sodium hydroxide NaHCO3 Sodium bicarbonate Na2CO3 Sodium carbonate NaNO2 Sodium nitrite NaOⁱPr Sodium isopropoxide NaH2PO4 Sodium dihydrogen phosphate NaIO4 Sodium periodate NBS N-bromo succinimide NH3 Ammonia N₂H₂ Diazene N₂H₄ Hydrazine NaNO2 Sodium nitrite _NMP N-Methyl-2-pyrrolidone _OsO4 Osmium tetroxide Pd(OAc)₂ Palladium(II) acetate Pd(PPh₃)₂Cl₂ Bis(triphenylphosphine)palladium(II) dichloride Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0) Pd(dppf)Cl₂ [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) P_d/C ^{Palladium on carbon} Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0) PhMe toluene PhNTF₂ Bis(trifluoromethanesulfonyl)aniline PPh3 Triphenylphosphine P(pMeOPh)₃ Tris(4-methoxyphenyl)phosphine PCy₃ Tricyclohexylphosphine PET ether Petroleum ether PMB Para-methoxybenzyl POBr3 Phosphoryl bromide; phosphorus oxybromide POCl3 Phosphoryl chloride; phosphorus oxychloride PivOH Pivalic acid PtBu3 tritertbutylphosphine PtO2 Platinum oxide PTSA p-toluenesulfonic acid Py, py Pyridine PyBOP (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate RBF Round-bottom flask RP Reverse phase rpm Revolutions per minute RT, rt Room temperature RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl SFC Supercritical fluid chromatography SOCl₂ Thionyl chloride T3P 1-Propanephosphonic anhydride TBAB Tetrabutylammonium bromide TEA Triethylamine tBuBrettPhos 2-(Di-tert-butylphosphino)-2′,4′,6′- triisopropyl-3,6- dimethoxy-1,1′-biphenyl tBuOH Tert-butyl alcohol tBuONO Tert-butyl nitrite tBuXPhos 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl ^tBuXPhos Pd G3 3^rd generation ^tBuXPhos palladium precatalyst TBAI Tetrabutylammonium iodide TBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate Tf2O Triflic anhydide TFA Trifluoroacetic acid TFBen Benzene-1,3,5-triyl triformate TMSCN Trimethylsilyl cyanide THF Tetrahydrofuran TLC Thin layer chromatography XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl Zn zinc References for the Synthesis of Building Blocks Building Block Reference Compound was prepared using the method described on page 308-311 of WO2022271727 A1. 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl- benzimidazol-2-one Compound was prepared using the method described on page 181-183 of WO2022271727 A1. 4-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl- benzimidazol-2-one Compound was prepared using the method described on page 270-272 of WO2021127586 A1. 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-l- methyl-lH-indazole Compound was prepared using the method described on page 278-279 of WO2023059792 A1 Compound was prepared using the method described on page 285-287 of WO2023059792 A1 EXAMPLE 1: SYNTHESIS OF TARGET LIGANDS Synthesis A1: Synthesis of 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (A-1)

Step-1: To a stirred solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1) (2.5 g, 9.90 mmol) and 2,2,2-trifluoroethanol (2) (990.65 mg, 9.90 mmol, 712.18 μL) in ACN (100 mL) was added DIPEA (1.92 g, 14.85 mmol, 2.59 mL) at -15 °C. Then reaction mixture was stirred at the same temperature for 30 minutes. The progress of reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed with water. The Layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford crude compound as a yellow gummy solid. The crude compound was purified by silica gel (100-200 mesh) column chromatography using ethyl acetate/petroleum ether as an eluent. The desired product was eluted in 3-4% ethyl acetate in petroleum ether. The desired product fraction was concentrated to afford 2,7-dichloro-8- fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (3) (2.5 g, 7.59 mmol, 76.69% yield, 96% purity) as a yellow solid. Mobile phase: (5% ethyl acetate:petroleum ether); Rf (Product): 0.4; Spot visualization: UV active compound; LCMS (ES+): m/z 315.97 [M+H]⁺; Retention time (min): 2.12. Step-2: To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (4) (906.73 mg, 5.70 mmol) in ACN (30 mL) was added DIPEA (1.23 g, 9.49 mmol, 1.65 mL) at room temperature and stirred for 5 minutes. After 5 minutes, 2,7-dichloro-8-fluoro-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.5 g, 4.75 mmol) was added to the reaction mixture at room temperature. The resulting reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with ethyl acetate (20 mL) and water (10 mL). The aqueous layer was separated, extracted with ethyl acetate (20 ml x 3). The organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford crude compound as a yellow gummy solid. The crude compound was purified by column chromatography, eluted in 35% ethyl acetate in petroleum ether, concentrated to afford 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (5) (1.25 g, 2.61 mmol, 55.08% yield, 91.76% purity) as a light yellow solid. Mobile phase: (50% ethyl acetate: petroleum ether); R_f (Product): 0.4; Spot visualization: UV active compound; LCMS (ES+): m/z 439.29 [M+H]⁺; Retention time (min): 1.38. Step-3: In a 10 mL vial a stirred solution of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (5) (1 g, 2.28 mmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (6) (1.23 g, 3.42 mmol) in tetrahydrofuran (20 mL) and water (1 mL) was added K3PO4 (1.45 g, 6.84 mmol) at room temperature under nitrogen gas. The reaction mixture was degassed with nitrogen for 15 minutes and CataCXium A Pd G3 (165.98 mg, 227.91 μmol) was added at room temperature. The reaction mixture was stirred at 65 °C for 2 hours while monitored by TLC and LCMS. The reaction mixture was evaporated under reduced pressure to obtain the crude compound. The obtained crude compound was purified by flash column chromatography using 100-200 silica, eluted with 0-70% ethyl acetate in petroleum ether to afford 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (A-1) (0.9 g, 1.05 mmol, 45.91% yield, 74% purity) as a yellow oil. Mobile phase: (50% ethyl acetate: pet ether); Rf (Product): 0.4; Spot visualization: UV active compound; LCMS (ES+): m/z 637.60 [M+H]⁺; Retention time (min): 1.85. Synthesis A2: Synthesis of 4-(4-(3-(aminomethyl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl- 6-fluoronaphthalen-2-ol (A-2):

Step-1: To a stirred solution of 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 785.44 mmol) in N,N-dimethylformamide (753.75 μL) was added DIPEA (203.02 mg, 1.57 mmol, 273.61 μL) at room temperature followed by the addition of tert-butyl N-(3-piperidylmethyl)carbamate (336.65 mg, 1.57 mmol) (1) and continued for 1 hour at 80 °C. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude compound. The crude material was adsorbed on silica gel and purified by silica gel (neutral alumina) column chromatography using 80% ethyl acetate in petroleum ether to afford tert-butyl N-[[1-[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-piperidyl]methyl]carbamate (2) (350 mg, 405.54 μmol, 51.63% yield, 87% purity) as a yellow gummy compound. R_f (Product): 0.3; Spot visualization: UV active compound; LCMS (ES+): m/z 751.84 [M+H]⁺; Retention time (min): 3.16. Step-2: To a stirred solution of tert-butyl N-[[1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-piperidyl]methyl]carbamate (2) (350 mg, 466.14 μmol) in dichloromethane (3 mL) was added HCl ^4.0 M in 1,4-dioxane ^ (17.00 mg, 466.14 μmol, 1.5 mL) drop wise at 0 °C and stirred for 2 hours at room temperature. Completion of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was evaporated under reduced pressure to obtain crude solid. The obtained crude solid was washed with pentane (30 mL) and concentrated under reduced pressure to afford the crude compound 4- [4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6-fluoro-naphthalen- 2-ol (A-2) (300 mg, 391.83 μmol, 84.06 % yield, 84.06% purity, hydrochloric acid) as a yellow solid. R_f (Product): 0.1; Spot visualization: UV active compound; LCMS (ES+): m/z 607.56 [M+H]⁺; Retention time (min): 2.41. Synthesis A3: Synthesis of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (A-3) Step-1: A stirred solution of benzyl N-(3-bromopropyl)carbamate (2) (313.15 mg, 1.15 mmol) in toluene (10 mL) was cooled to 0 °C and sodium hydroxide 50% (138.07 mg, 3.45 mmol) was added over the period of 5 minutes. Then tert-butyl (3R,5R)-3,5-dihydroxypiperidine-1- carboxylate (1) (0.250 g, 1.15 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The mixture was diluted with water (10 mL) and ethyl acetate (20 mL), then the organic layer was separated and washed with DI water (3 × 25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to afford the crude product. The crude product was then purified by flash silica gel (230-400) column chromatography, elution gradient 0 to 100% petroleum ether in ethyl acetate to obtain pure product tert-butyl 3-[3- (benzyloxycarbonylamino)propoxy]-5-hydroxy-piperidine-1-carboxylate (3) (0.168 g, 363.15 μmol, 31.56% yield, 88.3% purity) as a gummy liquid. Spot visualization: UV inactive compound KMnO₄ stain. LCMS (ES+): m/z 431.21 [M+Na]⁺; Retention time (min): 1.85. The stereochemistry for intermediates 3-6 and A-3 is relative trans stereochemistry at the piperidine (i.e., a mixture of (R)(R) and (S)(S) stereochemistry). Step-2: To a stirred solution of tert-butyl 3-[3-(benzyloxycarbonylamino)propoxy]-5-hydroxy- piperidine-1-carboxylate (3) (0.160 g, 391.69 μmol) in dichloromethane (1 mL) was added HCl ^4.0 M in 1,4-dioxane ^ (4 M, 1.00 mL) at 0 °C then the resulting reaction mixture was stirred at room temperature for two hours. The progress of reaction was monitored by TLC and LCMS. Observed desired product formation by LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure to afford crude product (0.160 g). The crude compound (0.160 g) was triturated with diethyl ether to afford benzyl N-[3-[[5-hydroxy-3- piperidyl]oxy]propyl]carbamate (0.150 g, 383.14 μmol, 97.82% yield, 88.08% purity, hydrochloric acid). Spot visualization: UV inactive compound KMnO4 stain. LCMS (ES+): m/z 309.32 [M+H] ⁺; Retention time (min): 1.13. Step-3: To a stirred solution of benzyl N-[3-[[5-hydroxy-3-piperidyl]oxy]propyl]carbamate (4) (0.677 g, 1.96 mmol, hydrochloric acid) in ACN (15 mL) was added molecular sieves (0.5 g, 785.44 μmol) followed by addition of Cs2CO3 (0.512 g, 1.57 mmol). The reaction mixture was stirred at room temperature for 10 minutes then 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4- (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (A-1) (0.5 g, 785.44 μmol) was added to the reaction mixture at the same temperature. The reaction mixture was stirred at room temperature for 12 hours. The progress of reaction was monitored by TLC and LCMS. The crude reaction mixture was purified by reverse phase chromatography to afford benzyl N-[3-[[1-[7-[8-ethyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-hydroxy-3- piperidyl]oxy]propyl]carbamate (5) (0.3 g, 332.73 μmol, 42.36% yield, 93.71% purity) as a colorless gummy. Mobile phase: (10% methanol: dichloromethane). Rf (Product): 0.4. Spot visualization: UV active compound. LCMS (ES+): m/z 845.65 [M+H]⁺; Retention time (min): 1.77. Step-4: To a stirred solution of benzyl N-[3-[[1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-hydroxy-3-piperidyl]oxy]propyl]carbamate (5) (0.3 g, 355.07 μmol) in methanol (3 mL) and ethyl acetate (3 mL) was added 10% palladium on carbon on 50 % wet basis (0.3 g, 355.07 mmol). The reaction mixture was stirred at room temperature for an hour under hydrogen bladder pressure. Reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was filtered through celite bed and washed with methanol: ethyl acetate (1:1, 10 mL x 3) to afford 5-(3-aminopropoxy)-1-[7-[8-ethyl-7-fluoro- 3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (0.250 mg, 60.56 μmol, 51.17% yield, 86.09% purity) as an off-white solid. Spot visualization: UV active compound; LCMS (ES+): m/z 711.72 [M+H]⁺; Retention time (min): 1.30. Step-5: To a stirred solution of (5-(3-aminopropoxy)-1-[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (6) (250 mg, 351.72 μmol) in dichloromethane (1.5 mL) was added HCl (4.0 M in 1,4-dioxane, 1.00 mL) at 0 °C. The reaction mixture was stirred at 25 °C for two hours, while monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure to afford crude product. The crude compound was triturated with diethyl ether (5 mL x 3) to afforded 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]piperidin-3-ol (A-3) (250 mg, 309.52 μmol, 88.00% yield, 87.06% purity, hydrochloric acid) as a light green solid. Spot visualization: UV active compound; LCMS (ES+): m/z 667.67 [M+H]⁺; Retention time (min): 1.27. Synthesis A4: Synthesis of [5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin- 4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1-yl-methanone (A-4) HN N Cbz O 5 O N HATU, TEA, DMF, N N 4M HCl in dioxane, N N 0°C to RT, 2h N DCM, 0°C to RT, 1h N Cbz N e_p-3 ^S Cbz S_t ^tep-4 NHBoc ⁶ NH_{2 7}

Step-1: To a stirred solution of methyl 5-bromo-1-methyl-pyrazole-3-carboxylate (1) (1 g, 4.57 mmol), (tert-butoxycarbonylamino)methyl-trifluoro-boron;potassium hydride (2) (1.62 g, 6.85 mmol) in dioxane (8 mL) and water (2 mL) was added cesium carbonate (148.75 mg, 456.55 μmol) at room temperature under nitrogen gas. The reaction mixture was degassed with argon for 10 minutes. After degassing, added Xphos (2.18 g, 4.57 mmol) and palladium (II) acetate (102.50 mg, 456.55 μmol) and stirred the reaction mixture at 80 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. Reaction mixture diluted with water (50 mL) and extracted with ethyl acetate (2 X 100 mL). The combined organic layer dried over sodium sulphate and concentrated under vacuum to obtain crude compound. The crude compound purified by column chromatography (silica 100-200, 50% ethyl acetate in pet ether) to afford methyl 5-[(tert-butoxycarbonylamino)methyl]-1-methyl-pyrazole-3-carboxylate (3) (600 mg, 1.85 mmol, 40.51% yield, 83% purity) as an off white solid. Mobile phase: (50 % Ethyl acetate in Petroleum ether); R_f (Product): 0.5; Spot visualization: UV active compound; LCMS (ES+): m/z 270.72 [M+H]⁺; Retention time (min): 2.11. Step-2: To a stirred solution of methyl 5-[(tert-butoxycarbonylamino)methyl]-1-methyl- pyrazole-3-carboxylate (3) (80 mg, 297.07 μmol) in THF (1 mL) and Water (1 mL) was added Lithium hydroxide monohydrate, 98% (62.33 mg, 1.49 mmol, 41.28 μL) The reaction was stirred at room temperature for two hours. The progress of reaction was monitored by TLC and LCMS. After completion of starting material, in reaction mixture water was added and acidified with 1N HCl to adjust PH 6 - 6.5, compound was extracted with ethyl acetate (2 X 10mL). The organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford crude compound, The crude compound was triturated with pet ether to afford 5-[(tert-butoxycarbonylamino)methyl]-1-methyl-pyrazole-3-carboxylic acid (4) (50 mg, 183.94 μmol, 61.92% yield, 93.91% purity) as off white solid. Mobile phase: (100 % Ethyl acetate in Petroleum ether); Rf (Product): 0.2; Spot visualization: UV active compound; LCMS (ES+): m/z 256.40[M+H] ⁺; Retention time (min):1.33. Step-3: To a stirred solution of 5-[(tert-butoxycarbonylamino)methyl]-1-methyl-pyrazole-3- carboxylic acid (4) (400 mg, 1.57 mmol) in N,N-dimethylformamide (8 mL) at 0 °C was added Triethylamine (47568 mg 470 mmol 65521 μL) followed by HATU (893.71 mg, 2.35 mmol). After 10 minutes, benzyl piperazine-1-carboxylate (5) (517.73 mg, 2.35 mmol, 453.35 μL) was added. Then reaction mixture was stirred at room temperature for two hours. The progress of reaction was monitored by TLC and LCMS. After completion of starting material reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 X 50 mL). Organic layer was concentrated under reduced pressure to afford crude compound. The crude compound was purified by using silica gel column chromatography (100/200 mesh, 100 % EA as a eluent) to afford benzyl 4-[5-[(tert-butoxycarbonylamino)methyl]-1-methyl-pyrazole-3- carbonyl]piperazine-1-carboxylate (6) (600 mg, 1.21 mmol, 77.20% yield, 92.24% purity) as yellow semi solid. Mobile phase: (100 % ethyl acetate in Petroleum ether); Rf (Product): 0.4; Spot visualization: UV active compound; LCMS (ES+): m/z 458.33 [M+H] ⁺; Retention time (min): 1.88. Step-4: To the stirred solution of benzyl 4-[5-[(tert-butoxycarbonylamino)methyl]-1-methyl- pyrazole-3-carbonyl]piperazine-1-carboxylate (600 mg, 1.31 mmol) in dichloromethane (6 mL) was added Hydrogen chloride solution, 4.0 M in dioxane HCl (4 M, 6 mL) at 0 °C and the reaction was stirred for an hour at room temperature. The reaction progress was monitored by TLC and LCMS. After completion of starting material the reaction mixture was concentrated under reduced pressure to afford crude product. The crude product was triturated with diethyl ether (50 ml) to afford benzyl 4-[5-(aminomethyl)-1-methyl-pyrazole-3-carbonyl]piperazine-1- carboxylate (7) (450 mg, 831.87 μmol, 63.43% yield, 72.81% purity, hydrochloric acid) as an off-white solid. Mobile phase: (10% methanol in dichloromethane); Rf (Product): 0.3; Spot visualization: UV active compound; LCMS (ES+): m/z 358.28 [M+H] ⁺; Retention time (min): 1.21. Step-5: To a stirred solution of benzyl 4-[5-(aminomethyl)-1-methyl-pyrazole-3- carbonyl]piperazine-1-carboxylate (7) (618.72 mg, 1.57 mmol, hydrochloric acid) in DMSO (5.09 mL) at room temperature was added Molecular sieves (500.00 mg, 1.14 mmol) followed by7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (A-1) (500 mg, 785.44 μmol) was stirred at 60 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion of starting material the reaction mixture was quenched with ice-cold water (30 mL) then filtered. The solid was dried under reduced pressure to afford crude product. The crude compound was purified by reverse phase column chromatography using C18 column (0-100% 0.1 % AMMONIUM BICARBONATE in water and ACN) to afford benzyl 4-[5-[[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazine-1-carboxylate (8) (370 mg, 319.82 μmol, 40.72% yield, 77.27% purity) as an off white solid. Mobile phase: (10% methanol : dichloromethane); Rf (Product): 0.4; Spot visualization: UV active compound; LCMS (ES+): m/z 894.84[M+H] ⁺; Retention time (min): 1.84. Step-6: To stirred solution of benzyl 4-[5-[[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido [4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazine-1-carboxylate (8) (340 mg, 380.33 μmol)n ethyl acetate (1 mL) and Methanol (1 mL) was added Palladium 10% on carbon (330 mg, 3.10 mmol) and stirred reaction mixture at room temperature for two hours under hydrogen bladder pressure. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was filtered through celite bed by using ethyl acetate (30 mL). The organic layer was evaporated under reduced pressure to afford crude compound. Crude compound was triturated with diethyl ether to afford [5-[[[7-[8-ethyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazol-3-yl]-piperazin-1-yl-methanone (290 mg, 269.80 μmol, 70.94% yield, 70.69% purity) as off white solid. Upon completion, the reaction mixture was filtered through celite bed and washed with methanol :ethyl acetate (1:1, 10 mL x 3) to afford (3S,5S)-5-(3-aminopropoxy)-1- [7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (9) (50 mg, 60.56 μmol, 51.17% yield, 86.09% purity) as an off white solid. Mobile phase: (10% methanol : dichloromethane); Rf (Product): 0.1; Spot visualization: UV active compound; LCMS (ES+): m/z760.51 [M+H] ⁺; Retention time (min): 1.39. Step-7: To a stirred solution of [5-[[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1-yl-methanone (9) (290 mg, 381.67 μmol) in dichloromethane (2.8 mL) was added HCl ^4.0 M in 1,4-dioxane ^ (4 M, 0.7 mL) at 0 °C. The reaction mixture was stirred at room temperature for an hour, while monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure to afford crude product. Then the crude compound was triturated with diethyl ether (3 X 5mL) to afford [5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1-yl-methanone (A-4) (280 mg, 288.33 μmol, 75.54% yield, 77.46% purity, hydrochloric acid) as a yellow solid. Spot visualization: UV active compound; LCMS (ES+): m/z 716.53[M+H] ⁺; Retention time (min): 2.38. Synthesis A5: Synthesis of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin- 4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (A-5)

Step-1: To a stirred solution of tert-butyl 4,6,7,8-tetrahydro-2H-pyrazolo[4,3-c]azepine-5- carboxylate (1) (5 g, 21.07 mmol) in dichloromethane (50 mL) was added CDI (6.83 g, 42.14 mmol) and benzyl piperazine-1-carboxylate (2) (6.96 g, 31.61 mmol, 6.10 mL). Reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was diluted with ice-cold water (100 mL) and extracted with dichloromethane (2 x 200 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford tert-butyl 2-(4-benzyloxycarbonylpiperazine-1-carbonyl)-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-5-carboxylate (3) (8 g, 12.99 mmol, 61.64% yield, 78.5% purity) as a yellow oil. Mobile phase: (50% ethyl acetate in pet ether); R_f (Product): 0.5; Spot visualization: UV active compound; LCMS (ES+): m/z 384.04 [M-Boc+H]⁺; Retention time (min): 2.78. Step-2: To a stirred solution tert-butyl 2-(4-benzyloxycarbonylpiperazine-1-carbonyl)-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-5-carboxylate (3) (5 g, 10.34 mmol) in dichloromethane (30 mL) was added hydrogen chloride (4.0M in 1,4-dioxane) (10 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4h, while monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure to afford crude product, which was triturated with diethyl ether (2 x 50 mL). The obtained solid was dried under reduced pressure to afford benzyl 4-(5,6,7,8-tetrahydro-4H- pyrazolo[4,3-c]azepine-2-carbonyl)piperazine-1-carboxylate (4) (4 g, 9.05 mmol, 87.52% yield, 95% purity, hydrochloric acid) as an off white solid. Step-3: To a stirred solution of benzyl 4-(5,6,7,8-tetrahydro-4H-pyrazolo[4,3-c]azepine-2- carbonyl)piperazine-1-carboxylate (4) (1.91 g, 4.56 mmol, hydrochloric acid) in N,N- dimethylformamide (10 mL) was added molecular sieves (1.0 g, 2.28 mmol) and DIPEA (883.63 mg, 6.84 mmol, 1.19 mL). The reaction mixture was stirred room temperature for 10 minutes and 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4- (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (5) (1.0 g, 2.28 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 70 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice-cold water (10 ml) to afford precipitated. A precipitated solid was filtered, which was washed with ethyl acetate (3 x 20 mL) to remove molecular sieves. The combined organic layer was evaporated under reduced pressure and purified by reverse phase column chromatography to obtain benzyl 4-[5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazine-1-carboxylate (6) (0.8 g, 906.47 μmol, 39.77% yield, 81.83% purity) as an off-white solid. Mobile phase: (10 % methanol in dichloromethane); R_f (Product): 0.4; Spot visualization: UV active compound; LCMS (ES+): m/z 722.51 [M+H]⁺; Retention time (min): 1.68. Step-4: To a stirred solution of benzyl 4-[5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazine-1-carboxylate (6) (0.4 g, 553.88 μmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (7) (299.28 mg, 830.82 μmol) in THF (8 mL), N,N-dimethylformamide (0.1 mL) and water (1.0 mL) at room temperature was added K₃PO₄ (470.28 mg, 2.22 mmol). The reaction mixture was degassed with nitrogen for 15 minutes. Then to the reaction mixture at room temperature was added cataxium® A Pd G3 (8067 mg 11078 μmol) The reaction mixture was stirred at 70 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was evaporated under reduced pressure to obtain crude compound. The crude compound was purified by flash column chromatography using 100-200 silica, eluted with 0-10% methanol in dichloromethane to afford benzyl 4-[5-[7-[8-ethyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazine-1-carboxylate (8) (0.5 g, 407.61 μmol, 73.59% yield, 75% purity) as a brown oil. Mobile phase: (10% methanol in dichloromethane); Rf (Product): 0.4; Spot visualization: UV active compound; LCMS (ES+): m/z 920.79 [M+H] ⁺; Retention time (min): 1.90. Step-5: To a solution of benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazine-1- carboxylate (8) (0.410 g, 445.66 μmol) in ethyl acetate (2 mL) and methanol (2 mL) was added 10% Palladium on carbon on 50% wet basis (410.00 mg, 3.85 mmol) at room temperature. Reaction mixture was stirred at room temperature for an hour under hydrogen bladder pressure, while monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed and washed with (1:1) mixture of methanol : ethyl acetate (3 x 10 mL), concentrated under reduced pressure to afford [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (9) (0.4 g, 389.89 μmol, 87.49% yield, 76.6% purity) as an yellow solid. Mobile phase: (one drop of aq. Ammonia in 10% methanol : dichloromethane); Rf (Product): 0.5; Spot visualization: UV active compound; LCMS (ES+): m/z 786.88 [M+H] ^+; Retention time (min): 1.93. Step-6: To a stirred solution of [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (9) (0.4 g, 509.00 μmol) in dichloromethane (2 mL) was added HCl ^4.0 M in 1,4-dioxane ^ (18.56 mg, 509.00 μmol, 1.5 mL)by dropwise at 0 °C. The reaction mixture was stirred at room temperature for two hours, while monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure to afford crude product, which was triturated with diethyl ether (15 mL) to afford [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (A-5) (0.380 g, 382.41 μmol, 75.13% yield, 78.32% purity, hydrochloric acid) as a yellow solid. Mobile phase: (one drop of aq. Ammonia in 10% methanol: dichloromethane); R_f (Product): 0.2; Spot visualization: UV active compound; LCMS (ES+): m/z 742.50 [M+H] ⁺; Retention time (min): 1.37. Synthesis A6: Synthesis of (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(piperazin-1-yl)methanone (A-6)

Step-1: To a stirred solution of 5-tert-butoxycarbonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylic acid (1) (1.0 g, 3.55 mmol) in N,N-dimethylformamide (10 mL) was added triethylamine (0.719 g, 7.11 mmol, 10 mL) and HATU (2.03 g, 5.33 mmol) at 0 °C. Reaction mixture was stirred at room temperature for 10 minutes and benzyl piperazine-1- carboxylate (2) (1.96 g, 8.89 mmol, 1.71 mL) was added to the reaction mixture at the same temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was diluted with ice-cold water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with ice-cold water (3 x 20 mL) and brine (20 mL), and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford tert-butyl 2-(4-benzyloxycarbonylpiperazine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-5-carboxylate (3) (1.5 g, 2.63 mmol, 74.00% yield, 84.80% purity) as a brown gummy compound. Mobile phase: (100 % ethyl acetate); R_f (Product): 0.4; Spot visualization: UV active compound; LCMS (ES+): m/z 484.39 [M+H]⁺; Retention time (min): 1.88 Step-2: To a stirred solution tert-butyl 2-(4-benzyloxycarbonylpiperazine-1-carbonyl)-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (3) (1.5 g, 3.10 mmol) in dichloromethane (10 mL) was added hydrogen chloride 4.0M 1,4-dioxane (4 M, 5 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for two hours, while monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure to afford crude product, which was triturated with diethyl ether (3 x 10 mL). The obtained solid was dried under reduced pressure to afford benzyl 4- (5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)piperazine-1-carboxylate (4) (1.2 g, 2.66 mmol, 85.91% yield, 93.25% purity, hydrochloric acid) as an off-white solid. Mobile phase: (10 % methanol in dichloromethane); R_f (Product): 0.3; Spot visualization: UV active compound; LCMS (ES+): m/z 385.01 [M+H]⁺; Retention time (min): 1.71. Step-3: To a stirred solution of benzyl 4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine- 2-carbonyl)piperazine-1-carboxylate (4) (0.956 g, 2.28 mmol, hydrochloric acid) in N,N- dimethylformamide (10 mL) was added molecular sieves (0.5 g, 1.14 mmol) and DIPEA (0.441 g, 3.42 mmol, 0.595 mL). The reaction mixture was stirred room temperature for 10 minutes and 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4- (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (5) (0.5 g, 1.14 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 70 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice-cold water (10 ml) to afford precipitate. The precipitated solid was filtered, which was washed with ethyl acetate (3 x 20 mL) to remove molecular sieves. The combined organic layer was evaporated under reduced pressure and purified by reverse phase column chromatography to obtain benzyl 4-[5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (6) (0.5 g, 0.573 mmol, 50.29% yield, 82.78% purity) as an off-white solid. Mobile phase: (10 % methanol in dichloromethane); R_f (Product): 0.3; Spot visualization: UV active compound; LCMS (ES+): m/z 722.45 [M+H]⁺; Retention time (min): 1.62. Step-4: To a stirred solution of benzyl 4-[5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo di i b l i i boxylate (6) (0.45 g, 623.11 μmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (7) (0.336 g, 934.67 μmol) in tetrahydrofuran (8 mL), N,N- dimethylformamide (0.2 mL) and water (1.0 mL) at room temperature was added K3PO4 (0.529 g, 2.49 mmol). The reaction mixture was degassed with nitrogen for 15 minutes. Then to the reaction mixture at room temperature was added cataxium® A Pd G3 (0.907 g, 124.62 μmol). The reaction mixture was stirred at 70 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was evaporated under reduced pressure to obtain crude compound. The crude compound was purified by flash column chromatography using 100-200 silica, eluted with 0-10% methanol in dichloromethane to afford benzyl 4-[5-[7- [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (8) (0.5 g, 478.27 μmol, 76.75% yield, 88% purity) as a brown oil. Mobile phase: (10% methanol in dichloromethane); Rf (Product): 0.4; Spot visualization: UV active compound; LCMS (ES+): m/z 920.75 [M+H]⁺; Retention time (min): 1.84. Step-5: To a solution of benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1- carboxylate (8) (0.5 g, 543.49 μmol) in ethyl acetate (2.5 mL) and methanol (2.5 mL) was added 10% palladium on carbon on 50% wet basis (0.5 g, 4.70 mmol) at room temperature. Reaction mixture was stirred at room temperature for two hours under hydrogen bladder pressure, while monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed and washed with (1:1) mixture of methanol: ethyl acetate (40 mL), concentrated under reduced pressure to afford [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (9) (0.420 g, 465.45 μmol, 85.64% yield, 87.09% purity) as an off-white solid. Mobile phase: (one drop of aq. ammonia in 10% methanol: dichloromethane); Rf (Product): 0.5; Spot visualization: UV active compound; LCMS (ES+): m/z 787.20 [M+H]⁺; Retention time (min): 1.88. Step-6: To a stirred solution of [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl- methanone (9) (0.5 g, 636.25 μmol) in dichloromethane (2 mL) was added HCl (4.0 M in 1,4- dioxane) (0.153 g, 4.21 mmol, 1 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for two hours, while monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure to afford crude product, which was triturated with diethyl ether (10 mL) to afford [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (0.480 g, 616.76 μmol, 96.94% yield, 86.66% purity, hydrochloric acid) as a yellow solid. Mobile phase: (one drop of aq. ammonia in 10% methanol: dichloromethane); Rf (Product): 0.2; Spot visualization: UV active compound; LCMS (ES+): m/z 742.51 [M+H]⁺; Retention time (min): 1.34. Synthesis A7: Synthesis of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin- 4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7)

Step-1: To a solution of ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2- carboxylate (2) (405.35 mg, 1.94 mmol) in N,N-dimethylformamide (5 mL) was added molecular sieves (30 mg, 774.88 μmol) and DIPEA (300.44 mg, 2.32 mmol, 404.90 μL) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes and 7-chloro- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (1) (340 mg, 774.88 μmol) was added to the reaction mixture at the same temperature. The reaction mixture heated to 70 °C and stirred for 16 hours. The progress of reaction was monitored by TLC and LCMS. Product formation was confirmed by LCMS. After consumption of starting material, ice-cold water (40 mL) was added to the reaction mixture to afford a solid, which was filtered and washed with ethyl acetate (50 mL x 2) to remove molecular sieves. Combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude compound which was purified by flash column chromatography using 100-200 silica gel eluted with 0-50% ethyl acetate in hexane, followed by 0-10% methanol in dichloromethane. Combined layers were evaporated to afford the desired compound ethyl 5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (3) (200 mg, 318.91 μmol, 41.16% yield, 87.38% purity) as an off-white solid. Rf: 0.4 (10% methanol in dichloromethane, UV detection). LCMS (ES+): m/z 746.43 [M+H]⁺; Retention time (min): 1.74. Step-2: To a stirred solution of ethyl 5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (3) (200 mg, 364.97 μmol) in tetrahydrofuran (3 mL) and water (0.5 mL) was added 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)- 1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4) (210.36 mg, 583.96 μmol) and potassium phosphate tribasic (232.42 mg, 1.09 mmol). The reaction mixture was degassed with argon for 5 minutes followed by addition of cataCXium® A Pd G3 (26.58 mg, 36.50 μmol) at room temperature, the resulting mixture was degassed again for 5 minutes and heated under stirring at 80 °C for 16 hours. Completion of the reaction was monitored by TLC and LCMS, Product formation was confirmed by LCMS. Crude compound was evaporated completely and purified by flash column chromatography using 100-200 silica, eluted with 0-60% ethyl acetate followed by 0-10% methanol in dichloromethane. The combined fractions were evaporated to afford the product ethyl 5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (5) (200 mg, 236.13 μmol, 64.70% yield, 88.05% purity) as yellow solid compound. Rf: 0.4 (10% methanol in dichloromethane, UV active). LCMS (ES+): m/z 746.54 [M+H]⁺ Retention time (min): 0.73. Step-3: To a solution of ethyl 5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (5) (600 mg, 804.52 μmol) in tetrahydrofuran (6 mL)added lithium hydroxide monohydride (33.76 mg, 804.45 μmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 hours. The progress of reaction was monitored by TLC and LCMS, product formation was confirmed by TLC. After the consumption of starting material, solvent was evaporated and crude compound was purified by reverse phase column chromatography using C18 cartridge, eluted with 0.1% ammonium bicarbonate in water and acetonitrile, combined fractions were evaporated to afford the product 5-[7-[8-ethyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[43-d]pyrimidin-4-yl]-467,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (6) (550 mg, 567.83 μmol, 70.58% yield, 74.10% purity) as an off-white solid. Rf: 0.4 (10% methanol in dichloromethane, UV active); LCMS (ES+): m/z 718.42 [M+H]⁺; Retention time (min): 1.63. Step-4: To a stirred solution of 5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (6) (550 mg, 766.30 μmol) in dichloromethane (4 mL) at 0 °C added HCl (4.0 M in 1,4-dioxane) (27.94 mg, 766.30 μmol, 2 mL) and stirred for 5 minutes at the same temperature and then stirred at 25 °C for 1 hour. The reaction progress was monitored by LCMS. Product formation was observed and confirmed by LCMS. After the consumption of starting material, the reaction mixture was concentrated under reduced pressure to afford crude product. The crude compound was triturated with diethyl ether (10 mL x 3) to afford 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (550 mg, 585.67 μmol, 76.43% yield, 75.62% purity, hydrochloric acid) as yellow colored solid. LCMS data: m/z 674.36 [M+H]⁺; Retention time (min): 1.48. Synthesis A8: Synthesis of benzyl 4-[5-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (A-8): To a stirred solution of benzyl 4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine- 2-carbonyl)piperazine-1-carboxylate (1) (759.41 mg, 1.98 mmol) in acetonitrile (6 mL) was added DIPEA (767.88 mg, 5.94 mmol, 1.03 mL) at 0 °C and stirred for 10 minutes at the same temperature, then 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (2) (500 mg, 1.98 mmol) was added at 0 °C and i d f h i progress was monitored by TLC and LCMS. After the consumption of starting material, the reaction mixture was concentrated completely under reduced pressure and was purified by flash column chromatography using 100-200 silica, eluted with 0-100% ethyl acetate. The combined fractions were evaporated to afford the product benzyl 4-[5-(2,7-dichloro-8-fluoro-pyrido[4,3- d]pyrimidin-4-yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1- carboxylate (A-8) (700 mg, 796.99 μmol, 40.24% yield, 68.25% purity) as light yellow solid. Rf: 0.5 (10% methanol in dichloromethane, UV active); LCMS (ES+): m/z 599.25 [M+H]⁺; Retention time (min): 2.06. Synthesis of ethyl 3-fluoro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate Step-1: To a solution of 5-(tert-butyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine- 2,5(6H)-dicarboxylate (1.0 equiv.) in acetonitrile was added Selectfluor^TM (5–10 equiv). The mixture was stirred at room temperature until the reaction was judged complete The mixture was concentrated and purified by prep-HPLC to afford 5-(tert-butyl) 2-ethyl 3-fluoro-7,8-dihydro- 4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate. Step-2: To a solution of 5-(tert-butyl) 2-ethyl 3-fluoro-7,8-dihydro-4H-pyrazolo[1,5- a][1,4]diazepine-2,5(6H)-dicarboxylate (1.0 equiv.) in dichloromethane/ trifluoroacetic acid (v/v = 1/1) was stirred at room temperature for 1 hour. The mixture was concentrated to afford ethyl 3-fluoro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate, which is directly used in next step without further purification. Synthesis of ethyl 3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate Step-1: To a solution of 5-(tert-butyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine- 2,5(6H)-dicarboxylate (1.0 equiv.) in N,N-dimethylformamide was added NCS (1.0–5.0 equiv.) at 0 ℃. The mixture was stirred at 55 ℃ until reaction was judged complete. The resulting reaction mixture was then subjected to a standard work up and purification to provide 5-(tert-butyl) 2-ethyl 3-chloro-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)- dicarboxylate. Step-2: To a solution of 5-(tert-butyl) 2-ethyl 3-chloro-7,8-dihydro-4H-pyrazolo[1,5- a][1,4]diazepine-2,5(6H)-dicarboxylate (1.0 equiv.) in dichloromethane/ trifluoroacetic acid (v/v = 1/1) was stirred at room temperature for 1 hour. The mixture was concentrated to afford ethyl 3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate, which is directly used in next step without further purification. Synthesis A9: Synthesis of 5-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4- yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-11)

O N OH N F N Cl Et N N O N F A-11 OH F Step-1: To a stirred solution of 2,2,2-trifluoroethanol 2 (302.81 mg, 3.03 mmol) in acetonitrile (10 mL) was added diisopropylethylamaine (494.05 mg, 3.82 mmol) at -15 °C and stirred for 10 minutes.7-bromo-2,4,6-trichloro-8-fluoro-quinazoline 1 (1 g, 3.03 mmol) was added and the resulting mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to get crude, which was purified by column chromatography (100-200 silica gel) using 5-8 % ethyl acetate in petroleum ether as an eluent to afford 7-bromo-2,6-dichloro-8- fluoro-4-(2,2,2-trifluoroethoxy)quinazoline 3 (1.1 g, 84% yield) as yellow solid. LCMS (ESI): m/z 395.23 [M+2H]⁺. Step-2: To a stirred solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol 4 (484.94 mg, 3.05 mmol) in tetrahydrofuran (2 mL) was added NaH ^60% dispersion in oil) (53.61 mg, 2.23 mmol) at -15 °C. The reaction mixture was stirred at the same temperature for 5 minutes. Then, 7-bromo-2,6-dichloro-8-fluoro-4-(2,2,2- trifluoroethoxy)quinazoline 3 (800 mg, 2.03 mmol) was added and the reaction mixture was stirred for 15 minutes. The reaction mixture was quenched with cold water and concentrated under reduced pressure to afford 7-bromo-6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)quinazoline 5 (0.8 g, 40% yield) as a yellow solid. LCMS (ESI) / 51827 [M+H]⁺ Step-3: To a stirred solution of ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2- carboxylate 6 (323.98 mg, 1.55 mmol) in dimethylformamide (10 mL) was added potassium carbonate (427.97 mg, 3.10 mmol) followed by addition of 7-bromo-6-chloro-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)- quinazoline 5 (800 mg, 1.55 mmol) at 0 ^oC. The reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated to get crude compound which was purified by column chromatography using (100-200 silica gel mesh) using 15% methanol in dichloromethane as eluent to afford ethyl 5-[7-bromo-6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]-diazepine-2-carboxylate 7 (430 mg, 44% yield) as a brown solid. LCMS [ESI]: m/z 627.55 [M+H]⁺. Step-4: To a stirred solution of ethyl 5-[7-bromo-6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 7 (200 mg, 319.54 μmol) and 2-[8-ethyl- 7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 8 (402.88 mg, 1.12 mmol) in a mixture of tetrahydrofuran (5 mL) and water (0.8 mL) was added potassium phosphate tribasic (71.32 mg, 1.28 mmol). The reaction mixture was degassed with nitrogen gas for 10 minutes and cataCXium® A Pd G3 (46.54 mg, 63.91 μmol) was added. The resulting reaction mixture was heated to and stirred at 80 °C for 2 hours. The reaction mixture was filtered, washed with dichloromethane and the filtrate was concentrated in vacuo to get the crude product which was purified by flash chromatography (100-200 silica gel) eluting with 3-5% methanol in dichloromethane to afford ethyl 5-[6-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]quinazolin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 9 (100 mg, 20% yield) as a colorless thick liquid. LCMS [ESI]: m/z 780.64 [M+H]⁺. Step-5: To a stirred solution of ethyl 5-[6-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]quinazolin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 9 (100 mg, 128.33 μmol) in a mixture of tetrahydrofuran (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (15.37 mg, 641.65 μmol) at 0 °C. The reaction mixture was stirred at room te f h h l d partially under reduced pressure, and the reaction mixture was acidified with citric acid solution. The solid was filtered and washed with water and dried under vacuum to afford 5-[6-chloro-7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylic acid 10 (75 mg, 78% yield) as an off white solid. LCMS (ESI): m/z 751.63 [M+H]⁺. Step-6: To a stirred solution of 5-[6-chloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]quinazolin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 10 (75 mg, 98.84 μmol) in dichloromethane (0.4 mL) at 0 °C was added 4 M HCl in 1,4-dioxane (0.1 mL) and the resulting reaction mixture was allowed to stir at room temperature for one hour and concentrated under reduced pressure to get crude which was triturated with diethyl ether to afford 5-[6-chloro-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-11 (70 mg, 75% yield, HCl salt) as yellow solid. LCMS (ESI): m/z 708.06 [M+H]⁺. The following compounds were prepared using the method described above in Synthesis A-11, with the corresponding aryl heterocycles in step-1. Aryl heterocycles Compound Structure Commercially available

Commercially available Commercially available Commercially available

Commercially available Commercially available WO2022171191, P47

CN115304623, P66 -70 CN115304623, P82 - 86

CN115304623, P73 - 77 WO2023061463, P56-57 Synthesis A10: Synthesis of ethyl 5-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (A-25)

Step-1: To a solution of methanol (1 -2 equiv.) in dry tetrahydrofuran was added NaH (60% in mineral oil, 2-5 equiv.) at 0 ℃. The resulting mixture was stirred at room temperature for half an hour before 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1) (1 equiv.) was added in one portion at 0 ℃. Then, the reaction mixture was allowed to stir at room temperature until the reaction was judged completed. The reaction mixture was quenched with cold sat. NH4Cl and then extracted with dichloromethane twice. The combined extracts were concentrated and purified by flash column chromatography to give 7-chloro-8-fluoro-5- methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (2). Step-2: To a solution of 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin- 4(3H)-one (2) (1 equiv.) in dry acetonitrile was added PyBop (2 -5 equiv.). After cooling to 0 ℃, ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (1–2 equiv.) and DBU (4–10 equiv.) was added dropwise, and then the resulting mixture was stirred at room temperature until the reaction was judged completed. The reaction mixture is subjected to standard workup condition to afford ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine- 2-carboxylate (3). Step-3: To a solution of ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2- carboxylate (3) (1 equiv.) in dichloromethane, m-CPBA (2-5 equiv.) was added at 0℃. The mixture was stirred at 0 ℃ until the reaction was judged completed. The result mixture was quenched by NaHCO₃ (aq.) and was subjected to the standard workup condition to afford ethyl 5-(7-chloro-8-fluoro-5-methoxy-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (4). Step-4: To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (4) (1– 2 equiv.) in dry tetrahydrofuran was added NaH (60% in mineral oil, 2–10 equiv.) at 0 ℃. The resulting mixture was stirred at room temperature for half an hour before a solution of ethyl 5- (7-chloro-8-fluoro-5-methoxy-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (1 euqiv.) in dry tetrahydrofuran was added dropwise at 0 ℃. The reaction mixture was continued stirred at 0 ℃ until the reaction was judged completed. The result mixture was quenched by NH₄Cl and then was subjected to the standard workup condition to afford ethyl 5-(7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (A-25). The following compounds were prepared using the method described above in Synthesis A10, with the corresponding alcohols in step-1. Alcohols Compound Structure EtOH iPrOH Cyclopropyl alcohol tBuOH Synthesis A11: Synthesis of ethyl 5-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (A-30)

Note: 1, CAS: 2892635-52-6 is prepared based on WO2023284537, p 119-121. Step-1: To a mixture of 1-benzyl-4,7-dichloro-8-fluoro-1,6-naphthyridin-2(1H)-one (1) (1 equiv.) and ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (1–2 equiv.) in dimethyl sulfoxide was added CsF (2 -5 equiv.) at room temperature, and the mixture was stirred at 60 ℃ until the reaction was judged completed. The reaction mixture was quenched with ice-water and subjected to standard workup condition to afford ethyl 5-(1-benzyl-7-chloro- 8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxylate (2). Step-2: A solution of ethyl 5-(1-benzyl-7-chloro-8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridin- 4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (2) (1 equiv.) in methanesulfonic acid (100–500 equiv.) was stirred at 80 ℃ until the reaction was judged completed. The reaction mixture was quenched with ice-water and subjected to standard workup condition to afford ethyl 5-(7-chloro-8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridin-4-yl)- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (3). Step-3: To a mixture of ethyl 5-(7-chloro-8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridin-4-yl)- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (3) (1 equiv.) in toluene were added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1–3 equiv.) and (tributylphosphoranylidene)acetonitrile (2–5 equiv ) at room temperature under N₂ atmosphere. The mixture was degassed under N₂ atmosphere for three-time sand stirred under N₂ atmosphere at 100 ℃ until the reaction was judged completed. The mixture was concentrated to dryness and the residue was purified by flash chromatography to give ethyl 5-(7-chloro-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (A-30). The following compounds were prepared using the method described above in Synthesis A11, with the corresponding carboxylic ester in step-3. Carboxylic Ester Compound Structure

Synthesis A12: Synthesis of 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-3-fluoro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A- 9) Step-1: To a solution of tert-butyl 2-(dimethylcarbamoyl)-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-5-carboxylate 1 (0.50 g, 1.62 mmol) in acetonitrile (10 mL) was added Selectfluor^TM (2.87 g, 8.11 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 72 hours The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with ethyl acetate and washed with water. The Layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to get crude compound tert-butyl 2- (dimethylcarbamoyl)-3-fluoro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate 2 (0.502 g, 535.43 μmol, 33.02% yield, 34.81% purity, no salt) as sticky white compound. LCMS [ES+]: m/z 327.43 [M+H]⁺. Step-2: To a stirred solution of tert-butyl 2-(dimethylcarbamoyl)-3-fluoro-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate 2 (8 mg, 24.51 μmol, no salt) in ethanol (0.5 mL) and water (0.5 mL) was added KOH (1.38 mg, 24.51 μmol) at 0 ℃. The resulting reaction mixture was stirred at 60 °C for 4 hours. The reaction mixture was concentrated to get the crude. The crude was dissolved in water (2 ml) and pH was neutralized to 7 by using 2 M HCl, then the compound was extracted with dichloromethane (10 mL × 5 times). The organic layer was dried over sodium sulphate, filtered, and concentrated to get the 5-tert-butoxycarbonyl- 3-fluoro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 3 (8 mg, 4.09 μmol, 16.69% yield, 15.31% purity, no salt) as sticky liquid. LCMS (ES+): m/z 300.22 [M-H]⁺ _. Step-3: To a stirred solution of 5-tert-butoxycarbonyl-3-fluoro-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylic acid 3 (8 mg, 26.73 μmol, No Salt) in ethanol (1 mL) was added H₂SO₄ (2.62 mg, 26.73 μmol) at 0 °C and allowed slowly to room temperature and stirred for 12 hours at 75 °C, Progress of the reaction was monitored by TLC and LCMS, product formation was observed and confirmed by LCMS. After the consumption of starting material, the reaction mixture was concentrated completely and quenched with saturated bicarbonate solution (5mL) and diluted with water and extracted with 10% methanol in dichloromethane (10mL × 3 times) and the combined organic layer was evaporated to get the desired compound ethyl 3-fluoro- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate 4 (5 mg, 3.37 μmol, 12.60% yield, 15.30% purity) as a yellow gummy compound. LCMS (ES+): m/z 228.19 [M+H]⁺ _. Step-4: To a stirred solution of ethyl 3-fluoro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxylate 4 (0145 g 0638 mmol) in N N-dimethylformamide (0.2 mL) was added molecular sieves (0.010g, 0.455 mmol), DIPEA (0.31 mL 1.82 mmol ) followed by the addition of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine 5 (0.20 g, 0.455 mmol ) at 0 ^oC. The resulting reaction mixture was heated to stir at 60 ^oC for 16 hours. The reaction mixture was concentrated under reduced pressure to get ethyl 5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-fluoro-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate ) 6 (0.082 g, 19 % yield) as a brown solid. LCMS (ES+): m/z 565.52 [M+H]⁺. Step-5: To a stirred solution of ethyl 5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-fluoro-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 6 (0.082 g, 0.144 mmol ) and 2-[8-ethyl- 7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.057 g, 0.159 mmol) in a mixture of tetrahydrofuran (1 mL) and water (0.1 mL) was added K3PO4 (0.092 g, 0.434 mmol), the resulting mixture was degassed with nitrogen gas for 10 minutes and catacxium® A Pd G3 (0.01g, 0.014 mmol) was added and heated to stir at 90 °C for 16 hours. The reaction mixture was filtered, washed with 5% methanol in dichloromethane and the filtrate was concentrated under reduced pressure to get crude ethyl 5-[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-fluoro-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 8 (0.050 g, 35% yield) as thick yellow liquid, LCMS (ES+): m/z 764.71 [M+H]⁺. Step-6: To a stirred solution of ethyl 5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-3-fluoro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 8 (0.05g, 0.065 mmol) in a mixture of tetrahydrofuran (1 mL) and water (0.1 mL) was added LiOH (47 mg, 0.196 mmol) at 0 ^oC. The resulting reaction mixture was allowed to stir at room temperature for 16 hours and concentrated under reduced pressure to get crude which was neutralized with 2M HCl and extracted with dichloromethane. The organic layer was dried over sodium sulphate, filtered, concentrated under reduced pressure to afford 5-[7-[8-ethyl-7-fluoro- 3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-fluoro-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 9 (0.040 g, 43% yield) as a pale yellow thick liquid. LCMS (ES+): m/z 736.2 [M+H]⁺. Step-7: To a stirred solution of 5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-3-fluoro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 9 (0.04 g, 0.054 mmol) in dichloromethane (2 mL) was added 4M HCl in 1,4 dioxane (0.013 mL,0.054 mmol) at 0 ^oC. The reaction mixture was allowed to stir at room temperature for an hour. The reaction mixture was concentrated under reduced pressure to get crude product which was triturated with pentane to afford 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-3-fluoro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-9 (35 mg, 41% yield, hydrochloric acid salt ) as a colorless thick liquid, LCMS (ES+): m/z 692.1 [M+H]⁺. Synthesis A13: Synthesis of 3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-10)

Step-1: To a stirred solution of 5-tert-butoxycarbonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylic acid 1 (2 g, 7.11 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (2.46 g, 17.77 mmol) at 0 °C and allowed to stir at room temperature for 30 minutes. Ethyl iodide (4.44 g, 28.44 mmol) was added and stirred for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to afford 5-(tert-butyl) 2-ethyl 7,8-dihydro- 4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate 2 (1.8 g, 65% yield) as an off white solid. LCMS (ES+): m/z 310.42 [M+H]⁺. Step-2: To a stirred solution of 5-(tert-butyl) 2-ethyl 7,8-dihydro-4H-pyrazolo[1,5- a][1,4]diazepine-2,5(6H)-dicarboxylate 2 (1.5 g, 4.85 mmol) in N,N-dimethylformamide (10 mL) were added NCS (2.59 g, 19.39 mmol) and the resulting reaction mixture was heated to stir at 60 ^oC for 10 minutes. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL), the combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated to get crude which was purified by flash column chromatography to afford 5-tert-butyl 2-ethyl 3-chloro-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2,5-dicarboxylate 3 (750 mg, 38% yield) as pale yellow thick liquid. LCMS (ES+): m/z 344.41 [M+H]⁺. Step-3: To a stirred solution of 5-tert-butyl 2-ethyl 3-chloro-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2,5-dicarboxylate 3 (500 mg, 1.45 mmol) in dichloromethane (2 mL) was added 4 M HCl in 1,4-dioxane (10.00 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for an hour. It was then concentrated under reduced pressure to get the crude which was triturated with diethyl ether to afford ethyl 3-chloro-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxylate 4 (363 mg,77% yield, hydrochloric acid salt) as an off white solid. LCMS (ES+): m/z 244.30 [M+H]⁺. Step-4: To a stirred solution of ethyl 3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxylate 4 (344.78 mg, 1.23 mmol, hydrochloric acid salt) in N,N- dimethylformamide (3 mL) was added molecular sieves (300 mg) and DIPEA (353.45 mg, 2.73 mmol). The reaction mixture was stirred at room temperature for 10 minutes and 7-chloro-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine 5 (300 mg, 683.72 μmol) was added to the reaction mixture and heated to stir at 70 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to get crude which was purified by flash column chromatography (silica gel,100-200) using 5-10% methanol in dichloromethane as an eluent to afford ethyl 3-chloro-5- [7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxylate 6 (180 mg, 43% yield) as a brown solid. LCMS (ES+): m/z 582.51 [M+H]⁺. Step-5: To a stirred solution of ethyl 3-chloro-5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 6 (180 mg, 309.05 μmol) and 2-[8-ethyl- 7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (222.66 mg, 618.10 μmol) in a mixture of tetrahydrofuran (2 mL) and water (0.5 mL) was added potassium phosphate tribasic (262.40 mg, 1.24 mmol) and degassed with argon for 5 minutes followed by addition of cataCXium® A Pd G3 (56.27 mg, 77.26 μmol).The reaction mixture was heated to stir at 70 °C for 12 hours. The reaction mixture concentrated under reduced pressure to get crude compound which was purified by column chromatography (100-200 silica) using 50-70% ethyl i l h l ff d hyl 3-chloro-5-[7-[8-ethyl- 7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo- [1,5-a][1,4]diazepine-2-carboxylate 8 (200 mg, 69% yield) as brown solid. LCMS (ES+): m/z 780.74 [M+H]⁺. Step-6: To a stirred solution of ethyl 3-chloro-5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]- pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 8 (200 mg, 256.33 μmol) in a mixture of tetrahydrofuran (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (48.40 mg, 1.15 mmol) at 0 °C. The resulting reaction mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to get crude product which was purified by reverse phase column chromatography (C18 cartridge) using 40-50% acetonitrile in 0.1% ammonium bicarbonate in water as an eluent to afford 3-chloro-5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 9 (100 mg, 38% yield) as an off white solid, LCMS (ES+): m/z 752.65 [M+H] ⁺. Step-7: To a stirred solution of 3-chloro-5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxylic acid 9 (100 mg, 132.95 μmol) in dichloromethane (0.5 mL) was added 4M HCl in 1,4-dioxane (0.1 mL) at 0 °C. The resulting reaction mixture was allowed to stir at room temperature for an hour. The reaction mixture was concentrated under reduced pressure to get crude which was triturated with diethyl ether to afford 3-chloro-5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxylic acid A-10 (85 mg, 54% yield, hydrochloric acid salt) as a yellow solid, LCMS (ES+): m/z 708.89 [M+H]⁺. Synthesis A14: Synthesis of 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8- difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4- yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-12) Step-1: To a stirred solution of ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2- carboxylate 2 (799.88 mg, 3.82 mmol) in acetonitrile (10 mL) was added diisopropylethylamaine (494.05 mg, 3.82 mmol) at 0 °C, followed by addition of 7-bromo-2,4-dichloro-6,8-difluoro- quinazoline 1 (800 mg, 2.55 mmol) and continued the stirring for an hour. The mixture was concentrated under reduced pressure to get the crude product which was triturated with diethyl ether to afford ethyl 5-(7-bromo-2-chloro-68-difluoro-quinazolin-4-yl)-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 3 (900 mg, 69% yield) as an off-white solid. LCMS (ESI): m/z 488.49 [M+2H]⁺. Step-2: To a stirred solution of ethyl 5-(7-bromo-2-chloro-6,8-difluoro-quinazolin-4-yl)-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 3 (700 mg, 1.44 mmol) in N,N- dimethylformamide (20 mL) was added cesium fluoride (1.75 g, 11.51 mmol) and [(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol 4 (686.92 mg, 4.31 mmol). The resulting mixture was heated to stir at 110 °C for 8 hours. The reaction mixture was concentrated under reduced pressure to get the crude which was purified by flash chromatography (silica gel 100- 200 mesh) eluting with 10% methanol in dichloromethane to afford ethyl 5-[7-bromo-6,8- difluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 5 (300 mg, 24% yield) as brown colored thick liquid. LCMS (ESI): m/z 611.49 [M+2H]⁺. Step-3: To a stirred solution of ethyl 5-[7-bromo-6,8-difluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylate 5 (300 mg, 492.26 μmol) and 2-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 6 (620.63 mg, 1.72 mmol) in a mixture of tetrahydrofuran (7.5 mL) and water (1.5 mL) was added potassium phosphate tribasic (417.97 mg, 1.97 mmol). The reaction mixture was degassed with nitrogen gas for 10 minutes and cataCXium® A Pd G3 (71.70 mg, 98.45 μmol) was added. The reaction mixture was heated to stir at 80 °C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to get crude which was purified by flash chromatography (silica gel 100-200 mesh) eluted at 3-5% methanol in dichloromethane to afford 5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 7 (200 mg, 42% yield) as an off white thick liquid. LCMS [ESI]: m/z 764.0 [M+H]⁺. Step-4: To a stirred solution of ethyl 5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]- 6,8-difluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 7 (100 mg, 131.10 μmol) in a mixture of tetrahydrofuran (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (27.50 mg, 655.49 l) h i i ll d stir at room temperature for 16 hours. The solvent was removed under reduced pressure, and the reaction mixture was acidified with citric acid solution. The precipitated solid was filtered, washed with water, and dried under vacuum to afford 5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-6,8- difluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 8 (80 mg, 75% yield) as an off white solid. LCMS (ESI): m/z 735.69 [M+H]⁺. Step-5: To a stirred solution of 5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-6,8- difluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 8 (80 mg, 108.88 μmol) in dichloromethane (0.4 mL) at 0 °C was added 4M HCl in 1,4-dioxane (0.3 mL). The resulting mixture was allowed to stir at room temperature for an hour. The reaction mixture was concentrated under reduced pressure to get crude which was triturated with diethyl ether to afford 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-6,8-difluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylic acid A-12 (70 mg, 78% yield, HCl salt) as yellow solid. LCMS (ESI): m/z 691.59 [M+H]⁺. EXAMPLE 2: SYNTHESIS OF BINDERS Synthesis B1: Synthesis of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dion (B-2)

O O H N B Br N _N ^O O OBn O O N OBn MeI, NaH, DMF ^N 8 Br N PdCl₂(dppf), N Step-6 OBn K₃PO₄, Dioxane: H₂O 7 B-1 Step-7 OBn Step-1: To a stirred solution of potassium tert-butoxide (22.76 g, 202.86 mmol) in tetrahydrofuran (150 mL) was added benzyl alcohol (19.50 g, 180.32 mmol, 18.66 mL) dropwise at 0 °C, and allowed to stir at room temperature for 1 hour. After completing, the resulting solution was added dropwise (30 min) into 2,6-dichloro-3-nitro-pyridine (1) (14.5 g, 75.13 mmol) in tetrahydrofuran (150 mL) at -20 °C (Light yellowish color was observed). The reaction mixture was allowed to stir for 15 minutes at -15 to -20 °C. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was poured into the ice water (300 mL) and stirred for 30 minutes. The yellow solid was obtained, which was filtered, washed with water (200mL) and dried under vacuum to afford 2,6-dibenzyloxy-3-nitro-pyridine (2) (24 g, 64.22 mmol, 85.47% yield, 90% purity) as a yellow solid. Mobile phase: (10% ethyl acetate in petroleum ether). RF (Product): 0.3; Spot visualization: UV active. Step-2: To a stirred solution of 2,6-dibenzyloxy-3-nitro-pyridine (2) (12 g, 35.68 mmol) in acetonitrile (120 mL) and water (12 mL) were added NiCl2·6H2O (1.70 g, 7.14 mmol) followed by NaBH₄ (2.70 g, 71.36 mmol, 2.51 mL) portion wise over a period of 30 minutes (exothermic was observed) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an hour. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (50 mL) brine (50 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated under reduced pressure to obtain the crude 2,6- dibenzyloxypyridin-3-amine (3) (6.5 g, 14.04 mmol, 39.36% yield, 66.18% purity) as a brown- colored liquid. Mobile phase: (20% ethyl acetate in petroleum ether); RF (Product): 0.6; Spot visualization: UV active; LCMS (ESI): m/z 306.78 (M+H)⁺; Retention time: 2.75 min. Step-3: To a stirred solution of 2,6-dibenzyloxypyridin-3-amine (3) (20 g, 65.28 mmol) in tetrahydrofuran (20 mL) at -78 °C, LiHMDS (1 M, 97.92 mL) was added dropwise over 15 minutes and allowed to stir at -78 °C for 2 hours. 4-bromo-1-fluoro-2-nitro-benzene (4) (14.36 g, 65.28 mmol, 8.04 mL) was added dropwise and stirred at room temperature for an hour. After completion, the reaction mixture was quenched with 10% NH₄Cl solution water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 10% ethyl acetate in petroleum ether as an eluent to afford 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (5) (9.5 g, 13.94 mmol, 21.36% yield, 74.32% purity). Mobile phase: (10% ethyl acetate in petroleum ether); RF (Product): 0.3; Spot visualization: UV active; LCMS(ES-): m/z 506.17 [M-H]-; Retention time: 1.35 min. Step-4: To a stirred solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (5) (8 g, 15.80 mmol) in acetonitrile (85 mL) and water (15 mL) were added NiCl₂·6H₂O (751.08 mg, 3.16 mmol) followed by NaBH4 (1.20 g, 31.60 mmol, 1.11 mL) portion wise over a period of 30 minutes (exothermic was observed) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an hour. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under reduced pressure to obtain the crude 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (6) (5.5 g, 10.39 mmol, 65.77% yield, 90% purity) as a brown-colored liquid. Mobile phase: (70% ethyl acetate in petroleum ether); R_F (Product): 0.6; Spot visualization: UV active; LCMS (ES-): m/z 474.23 [M-H]-; Retention time: 1.26 min. Step-5: To a stirred solution of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (6) (5.5 g, 11.55 m l) i di h lf id ( ) dded CDI (5.24 g, 32.33 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was poured into the ice water (300 mL) and stirred for 30 minutes. The off-white solid was obtained, which was filtered, washed with water (200 mL) and dried under vacuum to afford 6-bromo-3- (2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (7) (5.5 g, 7.20 mmol, 62.38% yield, 65.78% purity) as off white solid. Mobile phase: (40% ethyl acetate in petroleum ether); R_F (Product): 0.3; Spot visualization: UV active; LCMS(ES⁺): m/z 504.169 [M+H]⁺; Retention time: 2.55 min. Step-6: To a stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (7) (6.4 g, 12.74 mmol) in N,N-dimethylformamide (60 mL) was added NaH (1.43 g, 35.67 mmol, 60% purity) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 hour. After being stirred for 1 hour, the reaction mixture was cooled 0 °C and methyl iodide (2.71 g, 19.11 mmol, 1.19 mL) was added dropwise. The reaction mixture was allowed to stir at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured into the ice water (100 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under reduced pressure to afford the crude 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2- one (B-1) (4.2 g, 7.97 mmol, 62.60% yield, 98.05% purity) as off-white solid. Mobile phase: (70% ethyl acetate in petroleum ether); R_F (Product): 0.6; Spot visualization: UV active; LCMS (ES+): m/z 516.12 [M+H]⁺; Retention time: 7.27 min. Step-7: To a solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (B-1) (23 g, 44.54 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylate (9) (16.53 g, 53.45 mmol) in water (35 mL) and dioxane (350 mL) was added K2CO3 (18.47 g, 133.62 mmol) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes and Pd(dppf)Cl₂ DCM complex (3.64 g, 4.45 mmol) was added. The reaction mixture was allowed to stir at 90 °C for 16 hours. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash l h h i i il ili and 2% methanol in dichloromethane as eluent to afford tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2- oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (10) (24.5 g, 31.98 mmol, 71.81% yield, 80.77% purity) as brown solid. Mobile phase: (50% ethyl acetate in petroleum ether); R_F (Product): 0.4; Spot visualization: UV active; LCMS (ES+): m/z 619.462 (M+H)⁺; Retention time: 2.78 min. Step-8: To a stirred solution of tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (10) (22.5 g, 36.37 mmol) in tetrahydrofuran (250 mL) and ethyl acetate (250 mL) was added 10 % Pd on carbon (22.50 g, 211.43 mmol) at room temperature. The reaction mixture was stirred under hydrogen atmosphere (80 psi pressure) for 16 hours. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was filtered through celite bed and washed with ethyl acetate (200 mL). The filtrate was evaporated under reduced pressure to afford the crude tert- butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (11) (10.6 g, 22.39 mmol, 61.56% yield, 93.45% purity) as a gray-colored solid. Mobile phase: (50% ethyl acetate in petroleum ether); RF (Product): 0.6; Spot visualization: UV active; LCMS(ES+): m/z 441.27 [M-H]-; Retention time: 1.78 min. Step-9: To a stirred solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]piperidine-1-carboxylate (11) (3.5 g, 7.91 mmol) in dichloromethane (50 mL) was added TFA (26.08 g, 228.68 mmol, 17.50 mL) at 0 °C. After addition, reaction was warmed to room temperature and stirred for two hours. The completion of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was evaporated under reduced pressure and crude compound was triturated with diethyl ether (5 mL) to afford 3-[3-methyl-2-oxo-5-(4- piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (B-2) (3.6 g, 7.76 mmol, 98.10% yield, 98.37% purity, trifluoroacetic acid) as a pale green solid. Mobile phase: (methanol in dichloromethane); RF (Product): 0.1; Spot visualization: UV active; LCMS (ES+): m/z 343.24 [M+H]⁺; Retention time: 3.07 min; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 7.02-7.05 (m, 2H), 6.90 (d, J = 8.40 Hz, 1H), 5.35 (dd, J = 4.80, 12.40 Hz, 1H), 3.34-3.38 (m, 6H), 2.80- 3.10 (m, 4H), 2.60-2.70 (m, 2H), 1.94-1.98 (m, 3H), 1.77-1.80 (m, 2H). Synthesis B2: Synthesis of tert-butyl 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-2-oxoethyl)piperidine-1- carboxylate (B-3) To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (B-2) (0.2 g, 438.20 μmol, trifluoroacetic acid) and 2-(1-tert-butoxycarbonyl-4- piperidyl)acetic acid (1) (74.63 mg, 306.74 μmol) was added DIPEA (141.58 mg, 1.10 mmol, 190.81 μL) at 0 °C and stirred for 10 minutes, before adding HATU (249.92 mg, 657.30 μmol). After addition, reaction was warmed to room temperature and stirred for 2 hours. The progress of the reaction was monitored by LCMS and TLC. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 80 % ethyl acetate in petroleum ether as an eluent to afford tert-butyl 4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]-2-oxo-ethyl]piperidine-1-carboxylate (B-3) (175 mg, 302.05 μmol, 68.93% yield, 97.98% purity) as omethane); RF (Product): 0.3; Spot visualization: UV active; LCMS [ES+]: m/z 468.39 [M-Boc]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 11.08 (s, 1H), 7.10 (s, 1H), 7.01 (d, J = 8.00 Hz, 1H), 6.91 (d, J = 8.00 Hz, 1H), 5.34-5.31 (m, 1H), 4.62-4.54 (m, 1H), 4.01-3.92 (m, 1H), 3.90 (d, J = 6.80 Hz, 2H), 3.63-3.62 (m, 1H), 3.34 (s, 3H), 3.16-3.12 (m, 3H), 2.99-2.89 (m, 2H), 2.79-2.70 (m, 4H), 2.30-2.27 (m, 2H), 2.03-1.98 (m, 1H), 1.87-1.80 (m, 3H), 1.77 (d, J = 11.60 Hz, 2H), 1.39 (s, 9H),1.07-1.04 (m, 2H). Synthesis B3: Synthesis of tert-butyl 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-2-oxoethyl)piperazine-1- carboxylate (B-4) To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (B-2) (0.250 g, 547.75 μmol, trifluoroacetic acid) and 2-(4-tert- butoxycarbonylpiperazin-1-yl)acetic acid (1) (93.67 mg, 383.42 μmol) in N,N- dimethylformamide (5 mL) was added DIPEA (176.98 mg, 1.37 mmol, 238.52 μL) at 0 °C and stirred for 10 minutes, before adding HATU (312.40 mg, 821.62 μmol). After addition, reaction was warmed to room temperature and stirred for 2 hours. The progress of the reaction was monitored by LCMS and TLC. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 80 % ethyl acetate in petroleum ether as an eluent to afford tert-butyl 4-[2-[4- [1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-2-oxo- ethyl]piperazine-1-carboxylate (B-4) (0.18 g, 305.93 μmol, 55.85% yield, 96.65% purity) as a white solid. Mobile phase: (10 % methanol: dichloromethane); RF (Product): 0.3; Spot visualization: UV active; LCMS (ES+): m/z 569.47 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆): δ 11.08 (s, 1H), 7.08 (s, 1H), 7.02 (d, J = 8.00 Hz, 1H), 6.91 (d, J = 8.00 Hz, 1H), 5.76 (s, 1H), 5.36-5.31 (m, 1H), 4.51 (d, J = 12.40 Hz, 1H), 4.15 (d, J = 12.40 Hz, 1H), 3.32-3.31 (m, 4H), 3.30-3.11 (m, 2H), 3.07-2.71 (m, 3H), 2.64-2.59 (m, 1H), 2.40-2.39 (m, 4H), 2.01-1.98 (m, 2H), 1.79 (s, 2H), 1.66-1.63 (m, 1H), 1.55-1.50 (m, 1H), 1.39 (s, 9H), 1.26-1.24 (m, 3H). Synthesis B4: Synthesis tert-butyl 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]piperidine-1-carbonyl]piperidine-1-carboxylate (B-5) To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (B-2) (250 mg, 730.16 μmol) and 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (1) (150 mg, 654.24 μmol) in N,N-dimethylformamide (5 mL) was added DIPEA (253.67 mg, 1.96 mmol, 341.87 μL) at 0 °C and stirred for 10 minutes, before adding HATU (373.14 mg, 981.37 μmol). After addition, reaction was warmed to room temperature and stirred for 2 hours. The progress of the reaction was monitored by LCMS and TLC. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 80 % ethyl acetate in petroleum ether as an eluent to afford tert-butyl 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]piperidine-1-carbonyl]piperidine-1-carboxylate (B-5) (118.8 mg, 211.40 μmol, 32.31% yield, 98.52% purity) as off-white solid. Mobile phase: (100% ethyl acetate in petroleum ether); RF (Product): 0.4; Spot visualization: UV active. LCMS(ES+): m/z 454.40 [M-Boc]⁺; Retention time: 1.65; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 7.11 (s, 1H), 7.01 (d, J = 8.00 Hz, 1H), 6.92 (d, J = 8.00 Hz, 1H), 5.34 (dd, J = 5.20, 12.60 Hz, 1H), 4.56 (d, J = 12.80 Hz, 1H), 4.12 (d, J = 11.60 Hz, 1H), 3.94 (s, 2H), 3.32 (s, 3H), 3.12 (t, J = 11.60 Hz, 1H), 2.81-2.84 (m, 6H), 2.59 (s, 3H), 1.98-1.99 (m, 1H), 1.76-1.80 (m, 2H), 1.50-1.62 (m, 2H), 1.39(s, 12H). Synthesis B5: Synthesis of tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl)piperidin-1-yl)acetate (B-6) To a stirred solution of 3-[1-methyl-6-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione (B- 2) (0.250 g, 765.95 μmol) in N,N-dimethylformamide (4.00 mL) was added DIPEA (296.97 mg, 2.30 mmol, 400.23 μL) at 0° C and stirred for 10 minutes at same temperature. tert-butyl 2- bromoacetate (1) (179.28 mg, 919.14 μol, 134.80 μL) was added dropwise to the reaction mixture at 0 °C and allowed to stir at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice water (10 mL), precipitate formed was filtered, washed with pentane (10 mL) and dried under vacuum to afford the title compound tert-butyl 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]-1-piperidyl]acetate (B-6) (0.236 g, 516.32 μmol, 67.41% yield, 96.38% purity) as white solid. Mobile phase: (50 % ethyl acetate in petroleum ether); R_F (Product): 0.6; Spot visualization: UV active.; LCMS(ES+): m/z 441.40[M+H]⁺; Retention time: 1.20; ¹H NMR (400 MHz, DMSO-d₆): δ 10.88 (s, 1H), 7.60 (d, J = 8.40 Hz, 1H), 7.45 (s, 1H), 7.04 (dd, J = 8.60 Hz, 1H), 4.34-4.33 (m, 1H), 3.97 (s, 3H), 3.14 (s, 2H), 2.95 (d, J = 11.20 Hz, 2H), 2.67-2.55 (m, 3H), 2.37-2.30 (m, 3H), 2.18-2.14 (m, 1H), 1.83-1.71 (m, 4H), 1.45 (s, 9H). Synthesis B6: Synthesis of tert-butyl 2-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2- dihydrobenzo[cd]indol-6-yl)piperidin-1-yl)acetate (B-7) To a stirred solution of 3-[2-oxo-6-(4-piperidyl) benzo[cd]indol-1-yl]piperidine-2,6- dione (1) (0.130 g, 357.72 μmol) in N,N-dimethylformamide (2.05 mL) was added DIPEA (108.59 mg, 1.07 mmol, 149.58 μL) at 0° C and stirred for 10 minutes at same temperature. tert- butyl 2-bromoacetate (2) (83.73 mg, 429.27 μmol, 62.96 μL) was added dropwise to the reaction mixture at 0 °C and allowed to stir at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ice water (10 mL), precipitate formed was filtered, washed with pentane (20 mL) and dried under vacuum to afford the title compound tert-butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]-1-piperidyl]acetate (B-7) (0.107 g, 202.35 μmol, 56.57% yield, 90.31% purity) as pale yellow solid. Mobile phase: (50 % ethyl acetate in petroleum ether); R_F (Product): 0.6; Spot visualization: UV active; LCMS(ES⁺): m/z 478.39 [M+H]⁺; Retention time: 1.26; ¹H NMR (400 MHz, DMSO-d₆): δ 11.13 (s, 1H), 8.05 (d, J = 7.20 Hz, 1H), 7.84 (d, J = 8.80 Hz, 1H), 7.74- 7.68 (m, 1H), 7.54 (t, J = 7.60 Hz, 1H), 7.15 (d, J = 7.20 Hz, 1H), 5.47-5.42 (m, 1H), 3.40-3.39 (m, 1H), 3.19 (s, 2H), 3.01-2.81 (m, 3H), 2.80-2.73 (m, 2H), 2.63 (s, 1H), 2.50-2.45 (m, 2H), 2.10-2.07 (m, 1H), 1.95-1.85 (m, 3H), 1.45 (s, 9H). Synthesis B7: Synthesis of tert-butyl 2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)phenyl)piperidin-1-yl)acetate (B-8)

To a stirred solution of 1-[4-(4-piperidyl)phenyl]hexahydropyrimidine-2,4-dione (1) (0.210 g, 768.30 μmol) in N,N-dimethylformamide (2.09 mL) was added DIPEA (233.23 mg, 2.30 mmol, 321.26 μL) at 0 °C and stirred for 10 minutes at same temperature. tert-butyl 2- bromoacetate (2) (179.83 mg, 921.96 μmol, 135.21 μL) was added dropwise to the reaction mixture at 0 °C and allowed to stir at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice water (10 mL), precipitate formed was filtered, washed with pentane (20 mL) and dried under vacuum to afford tert-butyl 2-[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-1- piperidyl]acetate (B-8) (0.203 g, 508.14 μmol, 66.14% yield, 96.99% purity) as off-white solid. Mobile phase: (50 % ethyl acetate in petroleum ether); R_F (Product): 0.6; Spot visualization: UV active; LCMS(ES⁺): m/z 388.41[M+H]⁺; Retention time: 1.11; ¹H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 7.27-7.25 (m, 4H), 3.76 (t, J = 6.40 Hz, 2H), 3.32 (s, 2H), 2.93-2.91 (m, 2H), 2.70-2.69 (m, 2H), 2.46-2.44 (m, 1H), 2.31-2.28 (m, 2H), 1.65-1.63 (m, 4H), 1.42 (s, 9H). Synthesis B8: Synthesis of tert-butyl 2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1- yl)acetate (B-9) To a stirred solution of 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione (1) (0.25 g, 917.97 μmol) in N,N-dimethylformamide (2.00 mL) was added DIPEA (278.67 mg, 2.75 mmol, 383.84 μL) at 0° C and stirred for 10 minutes at same temperature. tert-butyl 2-bromoacetate (2) (214.86 mg, 1.10 mmol, 161.55 μL) was added dropwise to the reaction mixture at 0 °C and allowed to stir at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice water (10 mL), precipitate formed was filtered, washed with pentane (20 mL) and dried under vacuum to afford the title compound tert-butyl 2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]acetate (B-9) (0.24362 g, 624.74 μmol, 68.06% yield, 99.11% purity) as white solid. Mobile phase: (50 % ethyl acetate in petroleum ether); RF (Product): 0.6; Spot visualization: UV active. LCMS(ES+): m/z 387.38 [M+H]⁺; Retention i ¹ ( d ) δ 88 (s, 1H), 7.20 (d, J = 8 Hz, 2H), 7.13 (d, J = 8 Hz, 2H), 3.80 (t, J = 6.40 Hz, 1H), 3.11 (s, 2H), 2.95-2.84 (m, 2H), 2.70- 2.69 (m, 1H), 2.46-2.44 (m, 2H), 2.31-2.28 (m, 2H), 2.22-2.1 (m, 1H), 2.09-1.98 (m, 1H), 1.78- 1.58 (m, 4H), 1.42 (s, 9H). Synthesis B9: Synthesis of tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-7-yl)piperidin-1-yl)acetate (B-10) To a stirred solution of 3-[1-methyl-7-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione (1) (0.260 g, 796.59 μmol) in N,N-dimethylformamide (1.45 mL) was added DIPEA (617.72 mg, 4.78 mmol, 832.50 μL) at 0 °C and stirred for 10 minutes at same temperature. tert-butyl 2- bromoacetate (2) (186.45 mg, 955.91 μmol, 140.19 μL) was added dropwise to the reaction mixture at 0 °C and allowed to stir at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice water (10 mL), precipitate formed was filtered, washed with pentane (20 mL) and dried under vacuum to afford the title compound tert-butyl 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-7-yl]-1-piperidyl]acetate (B-10) (0.152 g, 340.03 μmol, 42.69% yield, 98.55% purity) as an off-white solid. Mobile phase: (50 % ethyl acetate in petroleum ether); R_F (Product): 0.6; Spot visualization: UV active. LCMS (ES+): m/z 441.44 [M+H]⁺; Retention time: 1.22; ¹H NMR (400 MHz, DMSO-d⁶): δ 10.88 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 6.8 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 4.35-4.32 (m, 1H), 4.20 (s, 3H), 3.27 (s, 1H), 3.17 (s, 2H), 2.95 (d, J = 11.20 Hz, 2H), 2.67-2.55 (m, 2H), 2.45-2.40 (m, 2H), 2.37-2.30 (m, 1H) 2.18-2.14 (m, 1H), 1.95-1.71 (m, 4H), 1.43 (s, 9H). Synthesis B10: Synthesis of tert-butyl 2-(4-(4-((2,6-dioxopiperidin-3- yl)oxy)phenyl)piperidin-1-yl)acetate (B-11) To a stirred solution of 3-[4-(4-piperidyl)phenoxy]piperidine-2,6-dione (1) (0.260 g, 901.71 μmol) in N,N-dimethylformamide (1.53 mL) was added DIPEA (349.62 mg, 2.71 mmol, 471.18 μL) at 0 °C and stirred for 10 minutes at same temperature. tert-butyl 2-bromoacetate (2) (211.06 mg, 1.08 mmol, 158.69 μL) was added dropwise to the reaction mixture at 0 °C and allowed to stir at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice water (10 mL), precipitate formed was filtered, washed with pentane (20 mL) and dried under vacuum to afford the title compound tert-butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]-1-piperidyl]acetate (B-11) (193.14 mg, 458.28 μmol, 50.82% yield, 95.50% purity) as an off-white solid. Mobile phase: (70 % ethyl acetate in petroleum ether); R_F (Product): 0.4; Spot visualization: UV active. LCMS (ES+): m/z 403.39 [M+H]⁺; Retention time: 1.20; ¹H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 7.15 (d, J = 8.80 Hz, 2H), 6.93 (d, J = 8.40 Hz, 2H), 5.13-5.12 (m, 1H), 3.11 (s, 2H), 2.90 (d, J = 11.20 Hz, 2H), 2.68-2.62 (m, 1H), 2.51-2.57 (m, 1H), 2.50-2.41 (m, 1H), 2.29- 2.26 (m, 2H), 2.13-2.11 (m, 2H), 1.59-1.58 (m, 4H), 1.42 (s, 9H). Synthesis B11: Synthesis of tert-butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-6-yl)piperidin-1-yl)acetate (B-12)

To a stirred solution of 1-[1-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine- 2,4-dione (1) (0.32 g, 977.46 μmol) in N,N-dimethylformamide (3.00 mL) was added DIPEA (296.73 mg, 2.93 mmol, 408.71 μL) at 0 °C and stirred for 10 minutes at same temperature. tert- butyl 2-bromoacetate (2) (228.79 mg, 1.17 mmol, 172.02 μL) was added dropwise to the reaction mixture at 0 °C and allowed to stir at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice water (10 mL), precipitate formed was filtered, washed with pentane (20 mL) and dried under vacuum to afford the title compound tert-butyl 2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]-1-piperidyl]acetate (B-12) (0.2125 g, 472.96 μmol, 48.39% yield, 98.27% purity) as white solid. Mobile phase: (50 % ethyl acetate in petroleum ether); R_F (Product): 0.6; Spot visualization: UV active. LCMS (ES+): m/z 441.40[M+H] ⁺; Retention time: 1.20; ¹H NMR (400 MHz, DMSO-d6): 10.53 (s, 1H), 7.54 (d, J = 8.40 Hz, 1H), 7.45 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.96 (S, 3H), 3.91 (t, J = 6.4 Hz, 2H), 3.14 (s, 2H), 2.95 (d, J = 10.8 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 2.62-2.57 (m, 1H), 2.34-2.28 (m, 2H), 1.78-1.74 (m, 4H), 1.43 (s, 9H). Synthesis B12: Synthesis of tert-butyl 2-(4-(4-(2, 6-dioxopiperidin-3-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-8-yl)piperidin-1-yl)acetate (B-13)

Step-1: To a stirred solution of 2-amino-6-bromo-phenol (1) (10 g, 53.19 mmol) in N,N- dimethylformamide (100.00 mL) was added K2CO3 (22.05 g, 159.56 mmol) and 1, 2- dibromoethane (11.99 g, 63.82 mmol, 5.50 mL) at 0 °C. The reaction mixture was stirred at 100 °C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was poured in the ice-cold water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under reduced pressure to provide crude compound, which was purified by column chromatography using Davisil silica and 30 % ethyl acetate in petroleum ether as eluent to afford 8-bromo-3,4-dihydro- 2H-1,4-benzoxazine (2) (4.3 g, 16.07 mmol, 30.22% yield, 80% purity) as dark reddish liquid. Mobile phase: (20 % ethyl acetate in petroleum ether); RF (Product): 0.2; Spot visualization: UV active. LCMS (ES+): m/z 215.93 [M+H]⁺; Retention time: 0.78 min. Step-2: To a stirred solution of 8-bromo-3,4-dihydro-2H-1,4-benzoxazine (2) (4.3 g, 20.09 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine- 1-carboxylate (3) (6.83 g, 22.10 mmol) in dioxane (80.22 mL) and water (20.05 mL) was added sodium carbonate (4.26 g, 40.18 mmol, 1.68 mL) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 minutes and Pd(dppf)Cl₂ (1.47 g, 2.01 mmol) was added. The reaction mixture was allowed to stir at 80 °C for 16 hours in sealed tube. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 30 % ethyl acetate in petroleum ether as an eluent to afford tert-butyl 4-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)-3,6-dihydro-2H- pyridine-1-carboxylate (4) (4.9 g, 15.13 mmol, 75.34% yield, 97.72% purity) as a light brown solid. Mobile phase: (30 % ethyl acetate in petroleum ether). R_F (Product): 0.3. Spot visualization: UV active. LCMS (ES+): m/z 317.32 [M+H]⁺; Retention time: 0.97 min. Step-3: To a solution of tert-butyl 4-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)-3,6-dihydro-2H- pyridine-1-carboxylate (4) (4.9 g, 15.49 mmol) and 2,6-dibenzyloxy-3-bromo-pyridine (5) (5.73 g, 15.49 mmol) was added NaO^tBu (390.81 mg, 4.07 mmol, 381.28 μL) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 minutes and Xanthphos (627.27 mg, 1.08 mmol) and Pd2(dba)3 (992.72 mg, 1.08 mmol) were added. The reaction mixture was allowed to stir at 100 °C for 16 hours in sealed tube. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 20 % ethyl acetate in petroleum ether as eluent to afford tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)-2,3-dihydro-1,4-benzoxazin-8-yl]-3,6-dihydro-2H- pyridine-1-carboxylate (6) (4.3 g, 6.78 mmol, 43.78% yield, 95.50% purity) as brown-colored liquid. Mobile phase: (40 % ethyl acetate in petroleum ether); RF (Product): 0.5; Spot visualization: UV active. LCMS (ES+): m/z 605.41[M+H] ⁺; Retention time: 1.42 min. Step-4: To a solution of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)-2,3-dihydro-1,4- benzoxazin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (5) (0.85 g, 1.40 mmol) in ethanol (10 mL) was added 10 % Pd on carbon (0.85 g, 7.18 mmol) at room temperature. The reaction mixture was stirred under hydrogen atmosphere (80 psi pressure) for 16 hours. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was filtered through celite bed and washed with ethyl acetate (20 mL). The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 50 % ethyl acetate in petroleum ether as an eluent to afford tert-butyl 4-[4-(2, 6-dioxo-3-piperidyl)-2, 3-dihydro-1, 4-benzoxazin-8-yl] piperidine-1- carboxylate (6) (0.3 g, 406.79 μmol, 28.99% yield, 58.24% purity) as an off white solid. Mobile phase: (60 % ethyl acetate in Petroleum ether); R_F (Product): 0.3; Spot visualization: UV active; LCMS (ES-) m/z: 428.00 [M-H]-; Retention time: 2.57 min. Step-5: To a stirred solution of tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)-2,3-dihydro-1,4- benzoxazin-8-yl]piperidine-1-carboxylate (7) (0.3 g, 698.47 μmol) in dichloromethane (3 mL) was added TFA (1.49 g, 13.07 mmol, 1.00 mL) at 0 °C. After addition, the reaction was warmed to room temperature and stirred for two hours. The completion of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was evaporated under reduced pressure and crude compound was triturated with diethyl ether (5 mL) to afford 3-[8-(4-piperidyl)-2,3- dihydro-1,4-benzoxazin-4-yl]piperidine-2,6-dione (8) (0.25 g, 338.28 μmol, 48.43% yield, 60% purity, trifluoroacetic acid). Mobile phase: (100 % ethyl acetate in petroleum ether); RF (Product): 0.2; Spot visualization: UV active. LCMS (ES+) m/z: 330.33 [M+H]⁺; Retention time: 0.37 min. Step-6: To a stirred solution of 3-[8-(4-piperidyl)-2,3-dihydro-1,4-benzoxazin-4-yl]piperidine- 2,6-dione (8) (0.4 g, 902.09 μmol, trifluoroacetic acid) in acetonitrile (5.49 mL) was added DIPEA (1.19 g, 9.19 mmol, 1.60 mL) at 0° C and stirred for 10 minutes at same temperature. tert-butyl 2-bromoacetate (9) (140.76 mg, 721.67 μmol, 105.84 μL) was added dropwise to the reaction mixture at 0 °C and allowed to stir at 70 °C for two hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 40 % ethyl acetate in petroleum ether as eluent to afford tert-butyl 2-[4-[4-(2,6-dioxo-3-piperidyl)-2,3-dihydro-1,4-benzoxazin-8-yl]-1-piperidyl]acetate (B-13) (92.5 mg, 196.66 μmol, 21.80% yield, 94.3% purity) as white solid. Mobile phase: (50 % ethyl acetate in petroleum ether); R_F (Product): 0.6˗Spot visualization: UV active. LCMS (ES+) m/z: 444.29 [M+H]⁺; Retention time: 5.88˗¹H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 6.68-6.67 (m, 2H), 6.48-6.47 (m, 1H), 4.87-4.86 (m, 1H), 4.16 (t, J = 4.40 Hz, 2H), 3.18-3.17 (m, 2H), 3.10 (s, 2H), 2.80-2.78 (m, 4H), 2.58-2.54 (m, 1H), 2.24-2.22 (m, 3H), 1.87-0.86 (m, 1H), 1.59-1.58 (m, 4H), 1.42 (s, 9H). Synthesis B13: Synthesis of tert-butyl 2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1,2- benzoxazol-6-yl]-1-piperidyl]acetate (B-14) To a solution of 1-[6-(4-piperidyl)-1,2-benzoxazol-3-yl]hexahydropyrimidine-2,4-dione (1) (0.23 g, 731.70 μmol) in N,N-dimethylformamide (5 mL) was added DIPEA (283.69 mg, 2.20 mmol, 382.34 μL) at 0° C and stirred for 10 minutes at same temperature. tert-butyl 2- bromoacetate (2) (171.26 mg, 878.03 μmol, 128.77 μL) was added dropwise to the reaction mixture at 0 °C and allowed to stir at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ice water (10 mL), precipitate formed was filtered, washed with pentane (10 mL) and dried under vacuum to afford tert-butyl 2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1,2-benzoxazol-6-yl]-1- piperidyl]acetate (B-14) (63.28 mg, 145.84 μmol, 19.93% yield, 98.75% purity) as off-white solid. Mobile phase: (10% methanol in dichloromethane); RF (Product): 0.3; Spot visualization: UV active. LCMS (ES+): m/z 429.35 [M+H]⁺ _; Retention time: 1.22; ¹H (400 MHz, DMSO-d₆): δ 10.88 (s, 1H), 7.75 (d, J = 8.40 Hz, 1H), 7.58 (s, 1H), 7.30 (d, J = 8.40 Hz, 1H), 4.05 (t, J = 6.40 Hz, 2H), 3.14 (s, 2H), 2.94 (d, J = 10.40 Hz, 2H), 2.78 (t, J = 6.40 Hz, 2H), 2.64-2.67 (m, 1H), 2.32 (t, J = 10.80 Hz, 2H), 1.60-1.90 (m, 4H), 1.43 (s, 9H). Synthesis B14: Synthesis of tert-butyl 2-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl)piperidin-4-yl)acetate (B-15) O O B^r _N O 2 N O N ^N _N N tBuXPhos Pd G3, NaOtBu Toluene, 100°C BnO BnO N Step-1 3 N 1 OBn OBn Step-1: To a solution of 6-bromo-3-(2, 6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1) (400 mg, 799.38 μmol) and tert-butyl 2-(4-piperidyl) acetate (2) (238.96 mg, 1.20 mmol) in toluene (5 mL) was added NaO^tBu (230.47 mg, 2.40 mmol, 224.85 μL) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 minutes and tBuXPhos Pd G3 (63.50 mg, 79.94 μmol) was added. The reaction mixture was allowed to stir at 100 °C for 16 hours in sealed tube. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 20 % ethyl acetate in petroleum ether as an eluent to afford tert-butyl 2-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-indazol-6-yl]-4-piperidyl]acetate (3) (0.210 g, 272.22 μmol, 34.05% yield, 80.21% purity) as colorless gum. Mobile phase: (30 % ethyl acetate in petroleum ether); R_F (Product): 0.3; Spot visualization: UV active; LCMS(ES+): m/z 619.70 [M+H]⁺; Retention time: 1.39 min. Step-2: To a stirred solution of tert-butyl 2-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol- 6-yl]-4-piperidyl]acetate (3) (0.200 g, 323.23 μmol) in ethyl acetate (2 mL), ethanol (2 mL) and tetrahydrofuran (2 mL) was added 10 % Pd on carbon (206.39 mg, 1.94 mmol) at room temperature. The reaction mixture was stirred under hydrogen atmosphere (balloon pressure) for 16 hours. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was filtered through celite bed and washed with ethyl acetate (20 mL). The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 50 % ethyl acetate in petroleum ether as a eluent to afford tert-butyl 2-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-4-piperidyl]acetate (B-15) (0.085 g, 192.95 μmol, 59.69% yield) as grey solid. Mobile phase: (70 % ethyl acetate in petroleum ether); R_F (Product): 03; Spot visualization: UV active; LCMS (ES+): m/z 441.29 [M+H]⁺; Retention time: 6.01 min; ¹H NMR (400 MHz, DMSO-d₆): δ 10.84 (s, 1H), 7.47 (d, J = 8.80 Hz, 1H), 6.89 (d, J = 9.20 Hz, 1H), 6.83 (s, 1H), 4.24 (dd, J = 5.20, 9.20 Hz, 1H), 3.88 (s, 3H), 3.76 (d, J = 12.40 Hz, 2H), 2.75-2.60 (m, 2H), 2.59-2.55 (m, 2H), 2.29-2.25 (m, 1H), 2.14-2.19 (m, 3H), 1.74-1.85 (m, 3H), 1.41 (s, 11H). Synthesis B15: Synthesis of tert-butyl 2-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)acetate (B-16) Step-1: To a solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one B-1 (0.700 g, 1.36 mmol) and tert-butyl 2-(4-piperidyl)acetate (1) (405.23 mg, 2.03 mmol) in toluene (10 mL) was added NaO^tBu (390.81 mg, 4.07 mmol, 381.28 μL) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 minutes and tBuXPhos Pd G3 (107.68 mg, 135.56 μmol) was added. The reaction mixture was allowed to stir at 100 °C for 16 hours in sealed tube. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 15% ethyl acetate in petroleum ether as eluent to afford tert-butyl 2-[1-[1-(2,6- dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]acetate (2) (0.450 g, 665.40 μmol, 49.09% yield, 93.86% purity) as colourless gum. Mobile phase: (70 % ethyl acetate in petroleum ether); R_F (Product): 0.3; Spot visualization: UV active; LCMS (ES⁺): m/z 636.10 [M+H]⁺; Retention time: 1.15 min. Step-2: To a stirred solution of tert-butyl 2-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-5-yl]-4-piperidyl]acetate (2) (0.450 g, 708.93 μmol) in tetrahydrofuran (5 mL) was added 10 % Pd on carbon (453.39 mg, 1.21 mmol) at room temperature. The reaction mixture was stirred under hydrogen atmosphere (balloon pressure) for 16 hours. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was filtered through celite bed and washed with ethyl acetate (20 mL). The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 50 % ethyl acetate in petroleum ether as an eluent to afford tert-butyl 2- [1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]acetate (B-16) (72.25 mg, 134.20 μmol, 18.93% yield, 84.80% purity) as grey solid. Mobile phase: (70 % ethyl acetate in petroleum ether); RF (Product): 0.3; Spot visualization: UV active; LCMS (ES⁺): m/z 457.37[M+H]⁺; Retention time: 1.30; ¹H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 6.92 (d, J = 8.80 Hz, 1H), 6.82 (s, 1H), 6.64-6.58 (m, 1H), 5.27-5.26 (m, 1H), 3.56 (d, J = 12.00 Hz, 2H), 3.30 (s, 3H), 2.85-2.89 (m, 1H), 2.62-2.59 (m, 4H), 2.18-2.17 (m, 2H), 1.98-1.99 (m, 1H), 2.17- 2.09 (m, 3H), 1.60-1.20 (m, 11H). Synthesis B16: Synthesis of tert-butyl 2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (B-17)

Step-1: To a solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (B-1) (0.8 g, 1.55 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1) (420.74 mg, 1.86 mmol) in toluene (10 mL) was added NaO^tBu (446.64 mg, 4.65 mmol, 435.75 μL) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 minutes and tBuXPhos Pd G3 (123.07 mg, 154.92 μmol) was added. The reaction mixture was allowed to stir at 100 °C for 16 hours in sealed tube. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 30% of ethyl acetate in petroleum ether to afford to afford tert-butyl 2-[1-(2,6- dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-2,7-diazaspiro[3.5]nonane-7- carboxylate (2) (470 mg, 703.38 μmol, 45.40% yield, 99.04% purity) as off white solid. Mobile phase: (70% ethyl acetate in petroleum ether); RF (Product): 0.3; Spot visualization: UV active. LCMS(ES⁺): m/z 662.51 [M+H]⁺; Retention time: 2.08. Step-2: To a stirred solution of tert-butyl 2-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (2) (0.47 g, 710.20 μmol) in ethanol (5 mL), tetrahydrofuran (5 mL), ethyl acetate (5 mL) was added 10 % Pd on carbon (500 mg, 4.70 mmol) at room temperature. The reaction mixture was stirred under hydrogen atmosphere (balloon pressure) for 16 hours. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was filtered through celite bed and washed with ethyl acetate (20 mL). The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 50 % ethyl acetate in petroleum ether as an eluent to afford tert-butyl 2-[1-(2,6-dioxo-3-piperidyl)-3- methyl-2-oxo-benzimidazol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (B-17) (60 mg, 101.47 μmol, 14.29% yield, 81.78% purity) as grey solid. Mobile phase: (70% ethyl acetate in petroleum ether); RF (Product): 0.3; Spot visualization: UV active. LCMS (ES⁺): m/z 484.31 [M+H]⁺; Retention time: 5.52 min. ¹H NMR (400 MHz, DMSO-d₆): δ 11.05 (s, 1H), 6.90 (d, J = 8.40 Hz, 1H), 6.27 (s, 1H), 6.10 (d, J = 8.00 Hz, 1H), 5.26 (dd, J = 4.80, 12.60 Hz, 1H), 3.55 (s, 5H), 3.30 (d, J = 19.20 Hz, 5H), 2.84-2.85 (m, 1H), 2.50-2.62 (m, 2H), 1.95-1.97 (m, 1H), 1.68 (s, 5H), 1.40 (s, 9H). Synthesis B17: Synthesis of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]piperazine-1-carboxylate (B-18) Step-1: To a solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (B-1) (0.8 g, 1.55 mmol) and tert-butyl piperazine-1-carboxylate (1) (346.25 mg, 1.86 mmol) in toluene (2 mL) was added ^tBuONa (446.64 mg, 4.65 mmol, 435.75 μL) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 minutes and tBuXPhos Pd G3 (123.07 mg, 154.92 μmol) was added. The reaction mixture was allowed to stir at 100 °C for 16 hours in sealed tube. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 30% of ethyl acetate in petroleum ether to afford to afford tert-butyl 4-[1-(2,6- dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazine-1-carboxylate (2) (420 mg, 608.46 μmol, 39.27% yield, 90.07% purity) as off white solid. Mobile phase: (70% ethyl acetate in petroleum ether); R_F (Product): 0.3; Spot visualization: UV active. LCMS (ES+): m/z 622.60 [M+H]⁺; Retention time: 1.24 min. Step-2: To a stirred solution of tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-5-yl]piperazine-1-carboxylate (2) (0.42 g, 675.54 μmol) in ethanol (5 mL), tetrahydrofuran (5 mL), ethyl acetate (5 mL) was added 10 % Pd on carbon (500 mg, 4.70 mmol) at room temperature. The reaction mixture was stirred under hydrogen atmosphere (balloon pressure) for 16 hours. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was filtered through celite bed and washed with ethyl acetate (20 mL). The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 50 % ethyl acetate in petroleum ether as an eluent to afford tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]piperazine-1-carboxylate (B-18) (35.45 mg, 58.42 μmol, 8.65% yield, 73.09% purity) as grey solid. Mobile phase: (70% ethyl acetate in Petroleum ether); RF (Product): 0.3; Spot visualization: UV active. LCMS (ES⁺): m/z 444.25 [M+H]⁺; Retention time: 5.21 min; ¹H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 6.77-6.97 (m, 2H), 6.66 (d, J = 8.40 Hz, 1H), 5.27-5.43 (m, 1H), 3.77-4.06 (m, 1H), 3.47 (s, 3H), 2.78-2.92 (m, 2H), 2.67-2.69 (m, 4H), 1.82- 1.99 (m, 2H), 1.42 (s, 12H). Synthesis B18: Synthesis of tert-butyl 4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]acetyl]piperidine-1-carboxylate (B-19) To a solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6- dione (1) (0.2 g, 584.13 μmol) in N,N-dimethylformamide (5 mL) was added DIPEA (452.96 mg, 3.50 mmol, 0.6 mL) at 0° C and stirred for 10 minutes at same temperature. tert-butyl 4-(2- bromoacetyl)piperidine-1-carboxylate (2) (214.63 mg, 700.95 μmol) was added dropwise to the reaction mixture at 0 °C and allowed to stir at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ice water (10 mL), precipitate formed was filtered, washed with pentane (10 mL) and dried under vacuum to afford tert-butyl 4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]acetyl]piperidine-1-carboxylate (B-19) (182.5 mg, 305.41 μmol, 52.29% yield, 95% purity) as an off white solid. Mobile phase: (10% methanol in dichloromethane); RF (Product): 0.3; Spot visualization: UV active. LCMS (ES+): m/z 568.442 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 7.10 (s, 1H), 7.01 (d, J = 8.00 Hz, 1H), 6.92 (d, J = 8.00 Hz, 1H), 5.36-5.31 (m, 1H), 3.92 (d, J = 11.20 Hz, 2H), 3.33-3.32 (m, 3H), 3.29 (s, 2H), 2.89-2.50 (m, 9H), 2.13-2.05 (m, 2H), 1.99-1.90 (m, 1H), 1.76-1.73 (m, 5H), 1.39-1.31 (m, 12H). Synthesis B19: Synthesis of tert-butyl N-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]ethyl]-N-methyl-carbamate (B-20) To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (1) (0.2 g, 584.13 μmol) in DCE (4 mL) and methanol (12 mL) were added sodium acetate (191.67 mg, 2.34 mmol, 125.44 μL), acetic acid (175.39 mg, 2.92 mmol) followed by tert-butyl N-methyl-N-(4-oxobutyl)carbamate (2) (202.35 mg, 1.17 mmol). The reaction mixture was stirred at room temperature for 3 hours. After being stirred for 3 hours, the reaction mixture was cooled to 0 °C, Si-CBH (270.86 mg, 4.67 mmol) was added, and it was allowed to stir at room temperature for two hours. The completion of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with water (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 5-10 % methanol in dichloromethane to afford tert- butyl N-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]ethyl]-N-methyl-carbamate (B-20) (105.3 mg, 205.04 μmol, 35.10% yield, 97.28% purity). Mobile phase: (10% methanol in dichloromethane); RF (Product): 0.3; Spot visualization: UV active. LCMS(ES⁺): m/z 500.44 [M+H]⁺; Retention time: 1.21; ¹H NMR (400 MHz, DMSO-d₆): δ 11.08 (s, 1H), 7.01-7.07 (m, 2H), 6.91 (d, J = 7.60 Hz, 1H), 5.34 (d, J = 8.40 Hz, 1H), 3.57-3.65 (m, 1H), 3.32 (s, 3H), 2.99-3.11 (m, 2H), 2.50-3.20 (m, 10H), 2.40-2.50 (m, 2H), 1.90-2.20 (m, 2H), 1.91 (s, 1H), 1.80-1.90 (m, 2H), 1.41 (s, 9H). Synthesis B20: Synthesis of tert-butyl N-[3-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]propyl]-N-methyl-carbamate (B-21) To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (1) (0.2 g, 584.13 μmol) in DCE (4 mL) and methanol (12 mL) were added sodium acetate (191.66 mg, 2.34 mmol, 125.43 μL), acetic acid (175.38 mg, 2.92 mmol) followed by tert-butyl N-methyl-N-(4-oxobutyl)carbamate (2) (218.74 mg, 1.17 mmol). The reaction mixture was stirred at room temperature for 3 hours. After being stirred for 3 hours, the reaction mixture was cooled to 0 °C, Si-CBH (270.85 mg, 4.67 mmol) was added, and it was allowed to stir at room temperature for two hours. The completion of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with water (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 5-10 % methanol in dichloromethane to afford tert- butyl N-[3-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]propyl]-N-methyl-carbamate (B-21) (127.9 mg, 239.65 μmol, 41.03% yield, 96.24% purity); Mobile phase: (10% methanol in dichloromethane); R_F (Product): 0.3; Spot visualization: UV active. LCMS (ES+): m/z 514.47 [M+H]⁺; Retention time: 1.26; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 7.03-7.05 (m, 2H), 6.91 (d, J = 7.60 Hz, 1H), 5.34 (dd, J = 5.20, 12.60 Hz, 1H), 3.20-3.40 (m, 5H), 2.95-3.15 (m, 2H), 2.80-2.90 (m, 2H), 2.79 (s, 3H), 2.64 (s, 3H), 2.40-2.45 (m, 1H), 2.25-2.35 (m, 1H), 1.60-2.10 (m, 8H), 1.40 (s, 9H). Synthesis B21: Synthesis of tert-butyl N-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]butyl]-N-methyl-carbamate (B-22) To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (1) (250 mg, 730.16 μmol) in DCE (4 mL) and methanol (12 mL) were added sodium acetate (239.58 mg, 2.92 mmol, 156.79 μL), acetic acid (219.23 mg, 3.65 mmol) followed by tert-butyl N-methyl-N-(4-oxobutyl)carbamate (2) (293.91 mg, 1.46 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. After being stirred for 3 hours, the reaction mixture was cooled to 0 °C, Si-CBH (1.03 g, 17.72 mmol) was added, and it was allowed to stir at room temperature for two hours. The completion of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with water (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 80 % ethyl acetate in petroleum ether as an eluent to afford tert-butyl N- [4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]butyl]-N- methyl-carbamate (B-22) (137.5 mg, 241.41 μmol, 33.06% yield, 92.64% purity). Mobile phase: (10% methanol in dichloromethane); RF (Product): 0.3; Spot visualization: UV active. LCMS(ES+): m/z 528.46 [M+H]⁺; Retention time: 1.31; ¹H NMR (400 MHz, DMSO-d₆): δ 11.07 (s, 1H), 7.09 (s, 1H), 7.00 (d, J = 8.00 Hz, 1H), 6.91 (d, J = 8.00 Hz, 1H), 5.33 (dd, J = 5.20, 12.40 Hz, 1H), 3.33 (s, 3H), 3.16 (t, J = 6.40 Hz, 2H), 2.80-3.00 (m, 3H), 2.76 (s, 3H), 2.60-2.70 (m, 2H), 2.29-2.30 (m, 2H), 0.93-1.96 (m, 3H), 1.84 (s, 1H), 1.67-1.71 (m, 4H), 1.45 (s, 13H). Synthesis B22: Synthesis of tert-butyl N-[3-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]propyl]-N-methyl-carbamate (B-23) To a stirred solution of -[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (1) (0.25 g, 730.16 μmol) in DCE (4 mL) and methanol (12 mL) were added sodium acetate (239.58 mg, 2.92 mmol, 156.79 μL), acetic acid (175.38 mg, 2.92 mmol) followed by tert-butyl N-methyl-N-(4-oxobutyl)carbamate (2) (331.93 mg, 1.46 mmol). The reaction mixture was stirred at room temperature for 3 hours. After being stirred for 3 hours, the reaction mixture was cooled to 0 °C, Si-CBH (338.56 mg, 5.84 mmol) was added, and it was allowed to stir at room temperature for two hours. The completion of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with water (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 5-10 % methanol in dichloromethane to afford tert-butyl 4-[2-[4-[1- (2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethyl]piperidine-1- carboxylate (B-23) (227 mg, 369.22 μmol, 50.57% yield, 90.06% purity) as a white solid. Mobile phase: (10% methanol in dichloromethane); RF (Product): 0.3; Spot visualization: UV active. LCMS(ES+): m/z 554.39 [M+H]⁺; Retention time: 5.7; ¹H NMR (400 MHz, DMSO-d₆): δ 11.08 (s, 1H), 7.02-7.07 (m, 2H), 6.91 (d, J = 7.60 Hz, 1H), 5.35 (dd, J = 7.20 Hz, 1H), 3.92 (d, J = 10.40 Hz, 2H), 3.34 (s, 3H), 2.80-3.30 (m, 4H), 2.50-2.70 (m, 6H), 2.40-2.50 (m, 1H), 1.38-2.20 (m, 20H), 1.00-1.02 (m, 2H). Synthesis B23: Synthesis of tert-butyl 4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (B- 24) To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (1) (0.2 g, 584.13 μmol) in DCE (4 mL) and methanol (12 mL) were added sodium acetate (191.67 mg, 2.34 mmol, 125.44 μL), acetic acid (35.08 mg, 584.13 μmol) followed by 4-formylpiperidine-1-carboxylate (2) (124.58 mg, 584.13 μmol). The reaction mixture was stirred at room temperature for 3 hours. After being stirred for 3 hours, the reaction mixture was cooled to 0 °C, Si-CBH (16929 mg 292 mmol) was added and it was allowed to stir at room temperature for two hours. The completion of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with water (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 80 % ethyl acetate in petroleum ether as an eluent to afford tert-butyl 4-[[4-[1- (2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]methyl]piperidine-1- carboxylate B-24 (0.107 g, 174.28 μmol, 29.84% yield, 87.90% purity). Mobile phase: (10 % methanol: dichloromethane); RF (Product): 0.3; Spot visualization: UV active. LCMS [ES+]: m/z 540.43 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 11.08 (s, 1H), 7.09 (s, 1H), 7.00 (s, 1H), 6.91 (s, 1H), 5.36-5.32 (m, 1H), 3.93 (d, J = 11.60 Hz, 2H), 3.34 (s, 3H), 2.93-2.90 (m, 2H), 2.87- 2.86 (m, 2H), 2.74-2.56 (m, 4H), 2.14 (s, 2H), 2.01-1.91 (m, 4H), 1.71 (s, 6H), 1.39 (s, 9H), 0.97 (s, 2H). Synthesis B24: Synthesis of tert-butyl 4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carbonyl)piperazine-1-carboxylate (B-25) Part-1: To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1- yl]piperidine-2,6-dione (1) (0.250 g, 730.16 μmol) in dichloromethane (10 mL) was added DIPEA (471.83 mg, 3.65 mmol, 635.89 μL) followed by triphosgene (108.34 mg, 365.08 μmol) at 0 °C. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quench d ith i t (5 L) d t t d ith di hloromethane (2 x 5 mL). The combined organic layer was evaporated under vacuum to afford the crude intermediate (part- 1). Part-2: The solution of tert-butyl piperazine-1-carboxylate (2) (135.99 mg, 730.16 μmol) in dichloromethane (5.0 mL) were added DIPEA (471.83 mg, 3.65 mmol, 635.89 μL) at 0 °C, followed by drop wise addition of crude intermediate (part-1) in dichloromethane (5.0 mL) and allowed to stir at room temperature for 30 minutes. The progress of the reaction was monitored by TLC. After completion of reaction, quenched with water (10 mL) and extracted with dichloromethane (2 x 10 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 80 % ethyl acetate in petroleum ether as an eluent to afford tert-butyl 4-[4-[1- (2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carbonyl]piperazine- 1-carboxylate (B-25) (0.072 g, 127.50 μmol, 17.46% yield, 98.22% purity) as a white solid. Mobile phase: (10 % methanol: dichloromethane); RF (Product): 0.3; Spot visualization: UV active. LCMS [ES-]: m/z 455.39 [M-Boc]-; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 7.10 (s, 1H), 7.02 (d, J = 8.00 Hz, 1H), 6.92 (d, J = 8.00 Hz, 1H), 5.36-5.31 (m, 1H), 3.73 (d, J = 12.80 Hz, 2H), 3.35-3.32 (m, 7H), 3.12 (s, 4H), 2.93-2.82 (m, 3H), 2.75-2.59 (m, 3H), 2.01-1.98 (m, 1H), 1.75 (d, J = 11.20 Hz, 2H), 1.68-1.62 (m, 2H), 1.41 (s, 9H). Synthesis B25: Synthesis of tert-butyl 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)ethyl)piperazine-1-carboxylate (B- 26)

Step-1: To a stirred solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (1) (1 g, 4.34 mmol) in dichloromethane (10mL) were added triethylamine (7.26 g, 71.75 mmol, 10 mL) and methanesulfonyl chloride (2) (596.87 mg, 5.21 mmol, 404.11 μL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under reduced pressure to afford crude tert-butyl 4-(2-methylsulfonyloxyethyl)piperazine-1- carboxylate (3) (1 g, 2.27 mmol, 52.27% yield, 70% purity) as a yellow gummy solid. The desired product was confirmed by ¹H NMR. Mobile phase: (10 % methanol: dichloromethane); RF (Product): 0.3; Spot visualization: UV active. Step-2: To a stirred solution of tert-butyl 4-(2-methylsulfonyloxyethyl)piperazine-1-carboxylate (3) (540.42 mg, 1.75 mmol) and 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1- yl]piperidine-2,6-dione (4) (0.2 g, 584.13 μmol) in N,N-dimethylformamide (5 mL) was added DIPEA (226.48 mg, 1.75 mmol, 305.23 μL) at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. The progress of the reaction was monitored by LCMS and TLC. After completion, the reaction mixture was quenched with water (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under reduced pressure and crude compound was purified by combi-flash column chromatography using Davisil silica and 5-10 % methanol in dichloromethane to afford tert-butyl 4-[2-[4-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethyl]piperazine-1-carboxylate B- 26 (0.062 g, 110.17 μmol, 18.86% yield, 98.56% purity) as white solid. LCMS(ES⁺): m/z 555.38 [M+H]⁺; Mobile phase: (10 % methanol: dichloromethane); R_F (Product): 0.3; Spot visualization: UV active. ¹H NMR (400 MHz, DMSO-d₆): δ 11.08 (s, 1H), 7.08-7.01 (m, 2H), 6.91 (d, J = 8.00 Hz, 1H), 5.36-5.32 (m, 1H), 3.00-2.86 (m, 11H), 2.74-2.70 (m, 6H), 2.50-2.33 (m, 6H), 2.07-1.98 (m, 2H), 1.84-1.74 (m, 3H), 1.46 (s, 9H). Synthesis B26: Synthesis of 3-(3-(piperidin-4-yl)phenoxy)piperidine-2,6-dione (B-27) Step-1: To a stirred solution of 3-bromophenol (1) (2 g, 11.56 mmol, No Salt) and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2) (3.57 g, 11.56 mmol) in water (30 mL) and 1,4-dioxane (3 mL) were added potassium phosphate tribasic(6.13 g, 28.90 mmol) and degassed with nitrogen for 10 minutes, then Pd(dppf)Cl2.CH2Cl2 (472.03 mg, 578.01 μmol) was added and the reaction mixture was again degassed for 5 minutes, resulted reaction mixture stirred for 16 hours at 90 °C. After complete consumption of starting material, reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 250 mL), organic layer separated was dried over sodium sulphate, concentrated under reduced pressure to afford crude compound, which was column purified using (Davisil silica) with 25 % ethyl acetate in petroleum ether as an eluent to afford tert-butyl 4-(3-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (3) (1.3 g, 4.02 mmol, 34.76% yield, 85.11% purity, no salt) as a yellow solid. LCMS (ES-): m/z 274.13 [M-H]-. Step-2: To a stirred solution of tert-butyl 4-(3-hydroxyphenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3) (1 g, 3.63 mmol) in Ethyl acetate (15 mL) and THF (15 mL) was added Pd/C (1.11 g, 10.39 mmol) and stirred the reaction mixture at 25 °C under hydrogen atmosphere in pare shaker (70 psi) for 16 hours. After completion of starting material, The reaction mixture was filtered through celite bed and washed with ethyl acetate (30 mL), concentrated under reduced pressure to afford crude compound which was purified using Davisil silica in 50% ethyl acetate in petroleum ether to afford tert-butyl 4-(3-hydroxyphenyl)piperidine-1-carboxylate (4) (1 g, 2.37 mmol, 65.22% yield, 65.70% purity, No Salt) as an off-white solid. LCMS (ES⁺): m/z 276.29 [M+H]⁺ Step-3: To a stirred solution of tert-butyl 4-(3-hydroxyphenyl)piperidine-1-carboxylate (4) (50 mg, 180.27 μmol) in N,N-dimethylformamide (3 mL) was added NaHCO₃ (8.65 mg, 360.55 μmol) and the reaction mixture was allowed to stir for 20 minutes at 50 °C. Then 3- bromopiperidine-2,6-dione (5) (276.91 mg, 1.44 mmol) was dissolved with minimum amount of N,N-dimethylformamide (3 mL) and the reaction mixture was heated to 70 °C for 16 hours. After complete consumption of the starting material, the reaction mixture was quenched with water and extracted product using ethyl acetate, dried over anhydrous sodium sulphate and concentrated under reduced pressure, to afford tert-butyl 4-(3-((2,6-dioxopiperidin-3- yl)oxy)phenyl)piperidine-1-carboxylate (6) (37 mg, 0.001619 mmol ,52.85% yield, 91.09% purity) as an off-white solid. LCMS (ES⁺): m/z 333.40 [M+H]⁺. Step-4: To the stirred solution of tert-butyl 4-(3-((2,6-dioxopiperidin-3- yl)oxy)phenyl)piperidine-1-carboxylate (6) (170 mg, 437.63 μmol) in dichloromethane (1 mL) was added HCl (4.0 M in 1,4-dioxane) (4 M, 109.41 μL) at 0 °C and the resulting reaction mixture was stirred for 1 hour at 25 °C . The reaction mixture was concentrated under reduced pressure to obtain crude compound. The crude product was triturated in diethyl ether (5 mL) to afford 3-(3-(piperidin-4-yl)phenoxy)piperidine-2,6-dione (B-27) (150 mg, 369.46 μmol, 84.42% yield, 80% purity, hydrochloric acid) as an off white solid. LCMS (ES⁺): m/z 289.34 [M+H]⁺.

3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- 2,6-dione (B-28) Compound 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione was prepared using the method described on page 119-122 of WO2023283610 A1. 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- 2,6-dione (B-29) Compound 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione was prepared using the method described on page 190-191 of WO2023019166 A1. 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- 2,6-dione (B-30) Compound 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione was prepared using the method described on page 167-170 of WO2023019166 A1. 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (B-31) Compound 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione was prepared using the method described on page 197 WO2021127586 Al. Synthesis B27: Synthesis of 3-[1-methyl-7-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione (B-32) Step-1: To a stirred solution of 7-bromo-1H-indazole 1 (20 g, 101.51 mmol) in N,N- dimethylformamide (200 mL) were added molecular iodine (51.42 g, 203.01 mmol) and KOH (11.39 g, 203.01 mmol, 5.57 mL) at 0 °C. The reaction mixture was stirred at room temperature for two hours. Upon completion of the reaction, the reaction mixture was diluted water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 7-bromo-3-iodo-1H-indazole 2 (30 g, 73.22% yield) as an off-white solid. LC-MS (ES⁺): m/z 322.47 [M+H]⁺. Step-2: To a stirred solution of 7-bromo-3-iodo-1H-indazole 2 (120 g, 371.60 mmol) in acetone (1000 mL) were added potassium hydroxide (41.70 g, 743.20 mmol, 20.40 mL) at 0 °C followed by methyl iodide (105.49 g, 743.20 mmol, 46.27 mL). The reaction mixture was then stirred at room temperature for 16 hours. Upon completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (Davisil silica, 3% Ethyl acetate in Pet ether as eluent) to afford 7-bromo-3-iodo-1-methyl-indazole 3 (85 g, 153.88 mmol, 41.41% yield) off white solid. LC-MS (ES⁺): m/z 337.08 [M+H]⁺. Step-3: To a solution of 7-bromo-3-iodo-1-methyl-indazole 3 (5 g, 14.84 mmol) and 2,6- dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 4 (6.19 g, 14.84 mmol) in water (36.00 mL) and dioxane (144.00 mL) was added tripotassium phosphate (9.45 g, 44.52 mmol) at room temperature. The reaction mixture was purged with argon gas for 10 minutes and tetrakis(triphenylphosphine)palladium(0) (1.71 g, 1.48 mmol) was added. The reaction mixture was purged with argon gas for an additional 5 minutes and then stirred at 95 °C for 4 hours. Subsequently, the reaction mixture was concentrated in vacuo and the crude compound was purified by column chromatography (Davisil silica, 2% ethyl acetate in petroleum ether as eluent) to afford 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 5 (2.5 g, 2.76 mmol, 18.58% yield) as an off-white solid. LC-MS (ES⁺): m/z 500.14 [M+H]⁺. Step-4: To a solution of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 5 (1.0 g, 2.00 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylate 6 (926.91 mg, 3.00 mmol) in dioxane (9.91 mL) and water (1.98 mL) was added sodium carbonate (529.54 mg, 5.00 mmol) at room temperature. The reaction mixture was purged with argon gas for 10 minutes before [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (163.20 mg, 199.85 μmol) was added and stirred at 80 °C for two hours. Upon completion of the reaction, the solvent was removed, and the residue was dissolved in water (150 mL) and extracted with ethyl acetate (3 × 75 mL). The combined organic layer was washed with brine and dried over sodi lf h d d ifi d b column chromatography (Davisil silica, 10% petroleum ether in ethyl acetate as eluent) to afford tert-butyl 4-[3-(2,6- dibenzyloxy-3-pyridyl)-1-methyl-indazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate 7 (1.1 g, 1.59 mmol, 79.69% yield) as a colorless oil. LC-MS (ES⁺): m/z 603.45 [M+H]⁺. Step-5: To a solution of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-7-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 7 (1.1 g, 1.83 mmol) in 1,4-dioxane (40 mL) was added Pd/C (1.11 g, 9.13 mmol) at room temperature and the reaction mixture was stirred at 25 °C for 16 hours under hydrogen atmosphere. Upon completion of the reaction, the reaction mixture was filtered through a pad of celite, which was then washed with ethyl acetate (150 mL). The combined filtrate was concentrated under reduced pressure to afford tert-butyl 4-[3-(2,6-dioxo- 3-piperidyl)-1-methyl-indazol-7-yl]piperidine-1-carboxylate 8 (0.65 g, 1.12 mmol, 61.57% yield) as an off-white solid. LC-MS (ES-): m/z 425.39 [M-H]-. Step-6: To a solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-7- yl]piperidine-1-carboxylate 8 (0.5 g, 1.17 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (1.34 g, 11.72 mmol, 903.18 μL). The reaction mixture was stirred at room temperature for 3 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford 3-[1-methyl-7-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione B-32 (0.45 g, 899.66 μmol, 76.74% yield, TFA salt) as a white solid. LC-MS (ES⁺): m/z 327.54 [M+H]⁺. 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (B- 33) Compound 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione was prepared using the method described on page 595-597 of WO2022261250 A1. Synthesis B28: Synthesis of 1-(1-methyl-7-(piperidin-4-yl)-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (B-34) Step-1: To the stirred solution of 1-(7-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (1) (0.30 g, 0.92 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2) (0.34 g, 1.11 mmol) in dioxane (5mL) and water (1 mL) was added potassium carbonate (0.384 g, 2.79 mmol). The reaction mixture was purged with nitrogen for 5 minutes and added Pd(dppf)Cl₂. DCM (0.037 g, 0.046 mmol). The reaction mixture was heated and stirred for 16 hours at 90 °C. Up On completion of reaction, the reaction mixture was concentrated under reduced pressure to afford crude compound which was purified by column (100-200 mesh) eluted in 70 % ethyl acetate in petroleum ether to afford tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3) (0.200 g, 323.26 μmol, 34.82% yield) as off-white solid. LCMS (ES⁺): m/z 426.51 [M+H]⁺. Step-2: To a stirred solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3) (0.200 g, 0.470 mmol) in methanol (5 mL) and ethyl acetate (15 mL) was added 10% palladium on carbon wet (0.064 g, 0.60 mmol) . The reaction mixture was stirred for 16 hours at 25 °C under hydrogen atmosphere (pare saker-60 psi). After complete consumption of the starting material, the reaction mixture was filtered using celite and filtrate was evaporated to afford tert-butyl 4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)piperidine-1-carboxylate (4) (0.060 g, 0.129 mmol, 30% yield, 92.04% purity) as white solid. LCMS (ES-): m/z 426.37 [M- H]- Step-3: To a stirred solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-7-yl)piperidine-1-carboxylate (4) (0.500 g, 1.17 mmol) in dichloromethane (2 mL)was added TFA (2.67 g, 23.39 mmol, 1.79 mL) at 25 °C and then the reaction mixture was stirred at 25 °C for 3 hours. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to afford of 1-(1-methyl-7-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (B-34) (0.450 g, 0.90 mmol, 77.24% yield, 88.62% purity) as an off-white solid. LCMS (ES⁺): m/z 328.42 [M+H]⁺. Synthesis B29: Synthesis of 3-[7-fluoro-2-methyl-6-(4-piperidyl)indazol-3-yl]piperidine- 2,6-dione (B-35) Step-1: To a stirred solution of 4-bromo-2, 3-difluoro-benzaldehyde (1) (11.8 g, 53.39 mmol) in 1,2 dimethoxyethane (240 mL), were added potassium carbonate anhydrous, 99% (8.86 g, 64.07 mmol, 3.87 mL) and methoxylamine hydrochloride (4.91 g, 58.73 mmol) then reaction mixture was stirred at 90 °C for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion, the mixture cooled and filtered through celite bed, washed bed with ethyl acetate (500 mL) and evaporated under reduced pressure. The crude compound was dissolved in 1,2- dimethoxyethane (240 mL), the reaction mixture was cooled to 0 °C and then hydrazine monohydrate, 98% (40.09 g, 800.91 mmol, 39.04 mL) was added dropwise and the reaction was stirred at 90 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure and quenched with cold water (300 mL) to afford solid. The obtained solid was filtered through the Buchner funnel, washed with water (500 mL) and dried to afford 6-bromo-7-fluoro-1H-indazole (2) (10.5 g, 47.10 mmol, 88.21% yield, 96.45% purity) as a white solid. LCMS (ES⁺): m/z 216.88 [M+2H]⁺. Step-2: To a stirred solution of 6-bromo-7-fluoro-1H-indazole (2) (10.5 g, 48.83 mmol) in acetonitrile (100 mL), was added potassium carbonate, anhydrous, 99% (20.25 g, 146.50 mmol, 8.84 mL) at 0 °C and stirred the reaction mixture at room temperature for half an hour. Then, iodomethane (10.40 g, 73.25 mmol, 4.56 mL) was added dropwise over the period of 10 minutes. Then the reaction mixture was stirred at 70 °C for 12 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was poured slowly into ice-cold water (300 mL) and extracted by ethyl acetate (150 mL x 2). The combined organic layer was dried over sodium sulphate, filtered, and concentrate under reduced pressure to obtain crude product, which was purified by column chromatography using silica gel (100-200 mesh, 30-40% ethyl acetate in petroleum ether as eluent) to afford 6-bromo-7-fluoro-2-methyl-2H- indazole (3) (4.0 g, 16.68 mmol, 34.16% yield, 95.52% purity) as off-white solid. LCMS (ES⁺): m/z 230.96 [M+2H]⁺. Step-3: To a stirred solution of 6-bromo-7-fluoro-2-methyl-indazole (3) (4.0 g, 17.46 mmol) in dimethyl sulfoxide (40 mL) was added N-iodosuccinimide (5.89 g, 26.20 mmol) and the reaction mixture was stirred at 90 °C for 12 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice-cold water (150 mL) to obtain solid, which was filtered and washed with the water (150 mL) and dried under high vacuum to afford 6-bromo-7-fluoro-3-iodo-2-methyl-indazole (4) (5.3 g, 13.59 mmol, 77.81% yield, 91% purity) as off-white solid. LCMS (ESI): m/z 355.89 [M+2H]⁺. Step-4: To a stirred solution of 6-bromo-7-fluoro-3-iodo-2-methyl-indazole (4) (5.2 g, 14.65 mmol) in water ( ) d di ( ) dd d -dibenzyloxy-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5) (9.17 g, 21.98 mmol) and potassium phosphate (9.33 g, 43.95 mmol) at room temperature. The reaction mixture was degassed with argon for 15 minutes before addition of Pd(PPh3)4 (1.69 g, 1.47 mmol) and the reaction mixture was stirred at 90 °C for 12 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled and evaporated to obtain crude product which was purified by column chromatography by using silica gel (60-120 mesh, 0-20% ethyl acetate in petroleum ether as eluent) to obtain 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-7-fluoro-2-methyl- indazole (6) (5.1 g, 7.33 mmol, 50.04% yield, 74.51% purity) as a yellow solid. LCMS [ES⁺]: m/z 518.07 [M+H]⁺. Step-5: To a stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-7-fluoro-2-methyl- indazole (6) (5.2 g, 10.03 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylate (7) (4.65 g, 15.05 mmol) in dioxane (50 mL) and water (10 mL) was added potassium carbonate, anhydrous, 99% (4.16 g, 30.09 mmol, 1.82 mL) at room temperature. The reaction mixture was degassed with argon for 15 minutes before addition of Pd(dppf)Cl2 (734.00 mg, 1.00 mmol) and the reaction mixture was stirred at 90 °C for 5 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was evaporated under reduced pressure to obtain crude product, which was purified by column chromatography by using silica gel (60-120 mesh, 0-20% ethyl acetate in petroleum ether as eluent) to afford tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-7-fluoro-2-methyl-indazol-6-yl]- 3,6-dihydro-2H-pyridine-1-carboxylate (8) (4.5 g, 5.68 mmol, 56.60% yield, 78.32% purity) as brown gummy solid. LCMS [ES+]: m/z 621.35 [M+H]⁺. Step-6: To the stirred solution of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-7-fluoro-2-methyl- indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (8) (3.1 g, 4.99 mmol) in dioxane (30 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (3.51 g, 24.97 mmol) and the reaction mixture was stirred at room temperature under hydrogen bladder atmosphere for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed and washed with ethyl acetate (300 mL). The filtrate was concentrated under reduced pressure to afford crude product, which was triturated with diethyl ether (500 mL) and to afford tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-7-fluoro-2- methyl-indazol-6-yl]piperidine-1-carboxylate (9) (2.1 g, 3.29 mmol, 65.92% yield, 69.68% purity) as a grey-colored solid. LCMS (ES-): m/z 442.82 [M-H]-. Step-7: To a stirred solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-7-fluoro-2-methyl- indazol-6-yl]piperidine-1-carboxylate (9) (0.4 g, 899.89 μmol) in dichloromethane (15 mL) was added TFA (4.62 g, 40.52 mmol, 3.10 mL) at 0 °C dropwise over the period of 5 minutes. followed by stirring at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure and co-distilled with tetrahydrofuran (10 mL) followed by triturated with diethyl ether (100 mL) to afford 3-[7-fluoro-2-methyl-6-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione (B- 35) (0.401 g, 798.67 μmol, 88.75% yield, 91.30% purity, trifluoroacetic acid) as off-white solid. LCMS (ES⁺): m/z 345.26 [M+H]⁺. Synthesis B30: Synthesis of 1-(6-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (B-37)

Step 1: To a solution of 6-bromopyrazolo[1,5-a]pyridine (1; 5 g, 25.38 mmol) in acetonitrile (70 mL) was added N-iodosuccinimide (5.71 g, 25.38 mmol) portion wise. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel, 230- 400 mesh) using 0-100% ethyl acetate in petroleum ether while the desired compound was eluted at 15% ethyl acetate in petroleum ether to afford 6-bromo-3-iodo-pyrazolo[1,5-a]pyridine (2; 7.2 g, 22.01 mmol, 86.7% yield, 98.73% purity) as an off-white solid. LCMS (ESI): m/z 322.8 [M+H]⁺; room temperature-1.09 min. Step 2: To a solution of hexahydropyrimidine-2,4-dione (3; 5 g, 43.82 mmol) and 1- (chloromethyl)-4-methoxy-benzene (8.92 g, 56.97 mmol) in N, N-dimethylformamide (100 mL), was added cesium carbonate (17.13 g, 52.58 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered and washed with N,N- dimethylformamide (10 mL). The filtrate was concentrated under reduced pressure, and the solid formed was treated with water and sonicated for 1 minute. The solid was filtered and washed with water (30 mL), ethyl acetate/petroleum ether (1:1 ratio, 2 x 20 mL), dichloromethane (20 mL) and dried under vacuum to give 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4- dione (4; 6.3 g, 26.17 mmol, 59.7% yield, 97.29% purity) as an off-white solid. LCMS (ESI): m/z 235.2 [M+H]⁺, room temperature-0.61 min. Step 3: To a solution of 6-bromo-3-iodo-pyrazolo[1,5-a]pyridine (2; 1.35 g, 4.13 mmol) and 3- [(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (4; 1.29 g, 5.37 mmol) in 1,4- dioxane (15 mL) was added potassium phosphate tribasic (2.19 g, 10.32 mmol). The contents were degassed with nitrogen for 5 minutes followed by the addition of (1R,2R)-(−)-1,2- diaminocyclohexane (117.83 mg, 1.03 mmol) and copper(I) iodide (196.52 mg, 1.03 mmol). The resulting mixture was heated at 90 °C for 16 hours The reaction mixture was treated with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine solution (40 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (Silica gel, 230-400 mesh) eluted with 50-60% ethyl acetate in petroleum ether to afford 1-(6-bromopyrazolo[1,5-a]pyridin-3-yl)-3-[(4- methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (5; 1.26 g, 2.72 mmol, 65.9% yield, 92.59% purity) as a brown solid. LCMS (ESI): m/z 429.0 [M+H]⁺; room temperature-0.97 min. Step 4: To a solution of 1-(6-bromopyrazolo[1,5-a]pyridin-3-yl)-3-[(4- methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (5; 1 g, 2.16 mmol) in 1,4-dioxane (15 mL) and water (3 mL), was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylate (6; 733.63 mg, 2.37 mmol) and potassium phosphate tribasic (915.71 mg, 4.31 mmol). The contents were degassed with nitrogen for 5 minutes followed by the addition of XPhos Pd G2 (169.71 mg, 215.69 μmol). The resulting mixture was stirred at 90 °C for two hours. The reaction mixture was treated with water (10 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (Silica gel, 230-400 mesh) eluted with 40-100% ethyl acetate in petroleum ether to afford tert-butyl 4-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1- yl]pyrazolo[1,5-a]pyridin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (7; 1.1 g, 1.94 mmol, 90.0% yield, 93.80% purity) as a pale brown solid. LCMS (ESI): m/z 532.2 [M+H]⁺; room temperature-3.07 min. Step 5: tert-Butyl 4-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1- yl]pyrazolo[1,5-a]pyridin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (3.20 g, 5.64 mmol) was taken in trifluoroacetic acid (44.40 g, 389.41 mmol, 30 mL), was added trifluoromethanesulfonic acid (10.25 g, 68.28 mmol, 6 mL). The resulting mixture was heated at 70 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and co-distilled with toluene (2 x 10 mL) to afford 1-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin- 3-yl]hexahydropyrimidine-2,4-dione trifluoroacetate (8; 2.4 g, 4.65 mmol, yield 82.4%, 82.39% purity) as a brown gum. LCMS (ESI): m/z 312.3 [M+H]⁺; room temperature-0.39 min. The crude product was taken to the next step without purification. Step 6: To a solution of 1-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridin-3- yl]hexahydropyrimidine-2,4-dione trifluoroacetate (8; 2.4 g, 6.35 mmol) in dichloromethane (63 mL), cooled to 0 °C, was added triethylamine (3.21 g, 31.76 mmol, 4.43 mL) followed by the addition of di-tert-butyl dicarbonate (1.39 g, 6.35 mmol, 1.46 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with water (20 mL) and extracted with 10% methanol in dichloromethane (2 x 100 mL). The combined organic phases were washed with brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (silica gel, 230-400 mesh) eluted with 0-100% ethyl acetate in petroleum ether while the desired compound eluted at 10% methanol in dichloromethane to give tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)pyrazolo[1,5- a]pyridin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (9; 2.4 g, 5.78 mmol, 91.05% yield, 99.135% purity) as an off-white solid. LCMS (ESI): m/z 412.2 [M+H]⁺; room temperature-2.63 min. Step 7: To a solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)pyrazolo[1,5- a]pyridin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (9; 1 g, 1.95 mmol) in 1,4-dioxane (40 mL), was added palladium hydroxide on carbon (20% dry basis, 700 mg, 1.95 mmol). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (~1 kg/cm²) for 16 hours. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (200 mL) and 1,4-dioxane/ethyl acetate (1:1 ratio, 1000 mL). The filtrate was concentrated under reduced pressure to give a crude product. The crude product was triturated with acetonitrile (10 mL), tetrahydrofuran (10 mL), and N,N-dimethylformamide (10 mL) followed by water (20 mL). The solid obtained was filtered and dried under vacuum to afford tert-butyl 4-[3-(2,4- dioxohexahydropyrimidin-1-yl)pyrazolo[1,5-a]pyridin-6-yl]piperidine-1-carboxylate (B-36; 1267.55 mg, 1.02 mmol, 52.4% yield, 96.17% purity) as an off-white solid. LCMS (ESI): m/z 358.2 [M-isobutene+H]⁺; room temperature-0.86 min.¹H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 8.48 (s, 1H), 7.98 (s, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.25 (dd, J = 9.2, 1.2 Hz, 1H), 4.12- 4.09 (m, 2H), 3.77 (t, J = 6.8 Hz, 2H), 2.79-2.67 (m, 5H), 1.83-1.80 (m, 2H), 1.62-1.51 (m, 2H), 1.43 (s, 9H) ppm. Step-8: To a solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)pyrazolo[1,5- a]pyridin-6-yl]piperidine-1-carboxylate in dichloromethane is added 4 M HCl in dioxane (10 equiv.) and the re i i i d f h Upon completion of the reaction, the solvent is removed under reduced pressure and the crude product is purified by column chromatography to afford 1-(6-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (B-37). Synthesis B31: Synthesis of 1-(7-(piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (B-39) Step 1: To a solution of 7-bromoimidazo[1,2-a]pyridine (1; 6 g, 30.44 mmol) and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2; 9.41 g, 30.44 mmol) in 1,4-dioxane (84 mL) and water (36 mL), was added potassium phosphate tribasic (12.92 g, 60.87 mmol). The contents were purged with nitrogen for 2 minutes. To this, was added XPhos Pd G2 (2.39 g, 3.04 mmol) and purged with nitrogen for 2 minutes. The resulting mixture was stirred at 100 °C for two hours. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the residue which was treated with water (10 mL) and extracted with ethyl acetate (3 x 60 mL) The combined organic phases were washed with brine solution (40 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (Silica gel, 230-400 mesh) eluted with 80-90% ethyl acetate in petroleum ether to give tert-butyl 4-imidazo[1,2-a]pyridin-7-yl-3,6-dihydro-2H-pyridine-1-carboxylate (3; 6 g, 20.04 mmol, 65.9% yield, 100% purity) as a brown solid. UPLC (ESI): m/z 300.5 [M+H]⁺, room temperature- 0.49 min. Step 2: To a solution of tert-butyl 4-imidazo[1,2-a]pyridin-7-yl-3,6-dihydro-2H-pyridine-1- carboxylate (3; 6 g, 20.04 mmol) in acetonitrile (150 mL), was added N-iodosuccinimide (4.51 g, 20.04 mmol) portion wise. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered and washed with acetonitrile (40 mL), and the solid was dried under vacuum to give tert-butyl 4-(3-iodoimidazo[1,2-a]pyridin-7-yl)-3,6-dihydro- 2H-pyridine-1-carboxylate (4; 6.5 g, 15.09 mmol, 75.30% yield, 65.9% yield, 98.74% purity) as a brown solid. UPLC (ESI): m/z 426.5 [M+H]⁺; room temperature-0.65 min. Step 3: To a solution of tert-butyl 4-(3-iodoimidazo[1,2-a]pyridin-7-yl)-3,6-dihydro-2H- pyridine-1-carboxylate (4; 2.5 g, 5.80 mmol) and 3-[(4- methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (5; 1.90 g, 8.13 mmol) in 1,4-dioxane (20 mL), was added potassium phosphate tribasic (2.46 g, 11.61 mmol). The contents were purged with nitrogen for 2 minutes. To this, were added (1R,2R)-(−)-1,2-diaminocyclohexane (132.57 mg, 1.16 mmol), copper (I) iodide (221.10 mg, 1.16 mmol) and the contents were purged with nitrogen for 2 min. The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue which was treated with water (10 mL) and extracted using ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (Silica gel, 230-400 mesh) eluted with 6-7% methanol in dichloromethane to give tert-butyl 4-[3-[3-[(4- methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]imidazo[1,2-a]pyridin-7-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (6; 2.4 g, 3.63 mmol, 62.5% yield, 80.41% purity) as a brown solid. UPLC (ESI): m/z 532.8 [M+H]⁺; room temperature-0.64 min. Step 4: tert-Butyl 4-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1- yl]imidazo[1,2-a]p idi l dih d idi b l (6; 1.1 g, 1.66 mmol) was taken in trifluoroacetic acid (14.80 g, 129.80 mmol, 10 mL), cooled to 0 °C, was added trifluoromethanesulfonic acid (3.42 g, 22.76 mmol, 2 mL). The resulting mixture was heated at 70 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and co-distilled with toluene (30 mL) to afford 1-[7-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3- yl]hexahydropyrimidine-2,4-dione trifluoroacetate (7; 1.28 g, 1.64 mmol, 98.5% yield, 54.47% purity) as a brown gum. UPLC (ESI): m/z 312.3 [M+H]⁺; room temperature-0.35 min. Step 5: To a solution of 1-[7-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3- yl]hexahydropyrimidine-2,4-dione trifluoroacetate (7; 1.28 g, 1.64 mmol) in dichloromethane (25 mL), cooled to 0 °C, was added triethylamine (1.66 g, 16.39 mmol, 2.28 mL) followed by addition of di-tert-butyl dicarbonate (357.74 mg, 1.64 mmol, 376.17 μL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 10% methanol in dichloromethane (500 mL) and washed with water (2 x 100 mL). The organic phase was washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (Silica gel, 230-400 mesh) eluted with 8-10% methanol in dichloromethane to afford tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2- a]pyridin-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (8; 0.77 g, 1.11 mmol, 67.8% yield, 59.41% purity) as a pale brown solid. LCMS (ESI): m/z 412.2 [M+H]⁺; room temperature-0.54 min. Step 6: To a solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2- a]pyridin-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (8; 0.9 g, 1.30 mmol) in 1,4 dioxane (40 mL), was added palladium hydroxide on carbon (20 wt. % dry basis, 0.56 g, 3.99 mmol). The resulting mixture was stirred at room temperature under a hydrogen atmosphere (~ 1 kg/cm²) for 16 hours. The reaction mixture was filtered through a pad of celite and washed with 1,4-dioxane in ethyl acetate (1000 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by prep HPLC [Column: X bridge C18 (150 x 10) mm 5 micron; Mobile phase: A: ammonium bicarbonate in water, B: Acetonitrile]. The fractions containing the product were lyophilized to afford tert-butyl 4-[3-(2,4- dioxohexahydropyrimidin-1-yl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate (B-38, 0.23 g, 555.05 μmol, 42.7% yield, 99.78% purity) as an off-white solid. LCMS (ESI): m/z 414.2 [M+H]⁺; room temperature-2.17 min.¹H NMR (400 MHz, DMSO-d6): δ 10.66 (s, 1H), 8.24 (d, J = 7.2 Hz, 1H), 7 ( ) ( ) (dd 1H), 4.12-4.09 (m, 2H), 3.79 (t, J = 6.4 Hz, 2H), 2.84-2.75 (m, 5H), 1.84-1.81 (m, 2H), 1.61-1.50 (m, 2H), 1.43 (s, 9H) ppm. Step-7: To a solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2- a]pyridin-7-yl]piperidine-1-carboxylate in dichloromethane is added 4 M HCl in dioxane (10 equiv.) and the reaction is stirred at room temperature for 16 hours. Upon completion of the reaction, the solvent is removed under reduced pressure and the crude product is purified by column chromatography to afford 1-(7-(piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (B-39). Synthesis B32: Synthesis of 3-methyl-3-[1-methyl-6-(4-piperidyl)indazol-3-yl]piperidine- 2,6-dione (B-42)

Step 1: To a solution of methyl 6-bromo-1H-indazole-3-carboxylate (1; 25 g, 98.01 mmol) in acetonitrile (800 mL) was added potassium carbonate (135.46 g, 980.13 mmol) and the resulting mixture was stirred at room temperature for 15 minutes. To this mixture, was added methyl iodide (69.56 g, 490.07 mmol, 30.51 mL) dropwise over 10 minutes. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (Silica gel, 230-400 mesh) eluted with 35-40% ethyl acetate in petroleum ether to give the regio-isomers, methyl 6-bromo-1-methyl-indazole-3- carboxylate (2; 17 g, 63.17 mmol, 64.5% yield, 100% purity) as an off-white solid. UPLC (ESI): m/z 269.0 [M+H]⁺; room temperature-0.93 min and methyl 6-bromo-2-methyl-indazole-3- carboxylate (3; 5 g, 18.22 mmol, 98.06% purity) as a pale-yellow solid. Yield-18.6%; UPLC (ESI): [M+H]⁺ m/z Calculated: 268.9, Found: 269.0; room temperature-1.10 min. Step 2: To a solution of methyl 6-bromo-1-methyl-indazole-3-carboxylate (2; 17 g, 63.17 mmol) in tetrahydrofuran (80 mL), cooled to 0 °C, was added diisobutylaluminium hydride (1 M in toluene, 16.95 g, 126.35 mmol, 126.35 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0 °C, treated with saturated ammonium chloride (100 mL), and extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed with water (150 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by flash chromatography (Silica gel, 230-400 mesh) eluted with 35-40% ethyl acetate in petroleum ether to give (6-bromo-1-methyl-indazol-3-yl)methanol (4; 15 g, 61.57 mmol, 97.5% yield, 98.96% purity) as an off-white solid. UPLC (ESI): m/z 241.4 [M+H]⁺, room temperature-0.63 min. Step 3: To a solution of (6-bromo-1-methyl-indazol-3-yl)methanol (4; 20 g, 82.96 mmol) in dichloromethane (150 mL), cooled to 0 °C, was added thionyl chloride (29.61 g, 248.88 mmol, 18.05 mL). The resulting mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with methyl tert-butyl ether (50 mL). The solid was filtered, washed methyl tert-butyl ether (3 x 20 mL) and dried under vacuum to give 6-bromo-3-(chloromethyl)-1-methyl-indazole (5; 20.5 g, 74.77 mmol, 90.13% yield, 90.1% yield, 94.66% purity) as an off-white solid. UPLC (ESI): m/z 260.2 [M+H]⁺; room temperature-1.03 min. The crude product was taken to the next without purification. Step 4: To a solution of 6-bromo-3-(chloromethyl)-1-methyl-indazole (5; 10 g, 38.53 mmol) in N, N-dimethylformamide (50 mL), was added sodium cyanide (3.78 g, 77.06 mmol). The resulting mixture was heated at 60 °C for 16 hours. The reaction mixture was cooled to room temperature, treated with water (50 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (Silica gel, 230-400 mesh) eluted with 30-40% ethyl acetate in petroleum ether to give 2-(6-bromo-1-methyl-indazol- 3-yl)acetonitrile (6; 8 g, 31.14 mmol, 80.8% yield, 97.34% purity) as an off-white solid. UPLC (ESI): m/z 250.2 [M+H]⁺; room temperature-0.87 min. Step 5: To a solution of 2-(6-bromo-1-methyl-indazol-3-yl)acetonitrile (6; 9.2 g, 36.42 mmol) in tetrahydrofuran (100 mL), cooled to -78 °C, was added potassium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 36.42 mL) dropwise over 10 minutes. The resulting mixture was stirred at - 78 °C for 1 hour. To this mixture, was added methyl iodide (4.65 g, 32.78 mmol, 2.04 mL) dropwise. The resulting mixture was stirred at -78 °C for 20 min. The reaction mixture was warmed to room te d ih d i hl ide solution (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with water (2 x 20 mL), 10% sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (Silica gel, 230-400 mesh) eluted with 35-40% ethyl acetate in petroleum ether to give 2-(6-bromo-1-methyl-indazol-3- yl)propanenitrile (7; 4.2 g, 15.57 mmol, 97.91% purity) as an off-white solid. Yield-42.8%; UPLC (ESI): [M+H]⁺ m/z Calculated: 264.0, Found: 263.9; room temperature-0.96 min and 2- (6-bromo-1-methyl-indazol-3-yl)-2-methyl-propanenitrile (8; 1.7 g, 5.21 mmol, 14.3% yield, 85.28% purity) as a pale brown color solid. UPLC (ESI): m/z 279.7 [M+H]⁺; room temperature- 1.05 min. Step 6: To a solution of 2-(6-bromo-1-methyl-indazol-3-yl)propanenitrile (7; 7.5 g, 27.82 mmol) in 1,4-dioxane (100 mL) were added methyl acrylate (9; 4.79 g, 55.64 mmol, 5.01 mL), cooled to 0 °C, was added benzyltrimethylammonium hydroxide (40% in water, 5.82 g, 13.91 mmol, 6.12 mL). The resulting mixture was stirred at room temperature for two hours. The reaction mixture was treated with saturated ammonium chloride solution (20 mL) at 0 °C and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with brine solution (20 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give methyl 4-(6-bromo-1-methyl-indazol-3-yl)-4-cyano-pentanoate (10; 9.5 g, 14.40 mmol, 51.8% yield, 53.10% purity) as a yellow oil. UPLC (ESI): m/z 350.0 [M+H]⁺; room temperature-1.04 min. Step 7: To a solution of methyl 4-(6-bromo-1-methyl-indazol-3-yl)-4-cyano-pentanoate (10; 9.5 g, 27.13 mmol) in water (10 mL) and methanol (80 mL), cooled to 0 °C, was added sodium hydroxide (10 M in water, 10.85 mL). The resulting mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure to remove organic volatiles, acidified with 1.5 N hydrochloric acid, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine solution (30 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 4-(6-bromo-1-methyl-indazol-3-yl)-4-cyano-pentanoic acid (11; 8.5 g, 25.01 mmol, 92.2% yield, 98.92% purity) as an off-white solid. UPLC (ESI): m/z 336.1 [M+H]⁺; room temperature- 0.53 min. Step 8: To a solution of 4-(6-bromo-1-methyl-indazol-3-yl)-4-cyano-pentanoic acid (11; 10 g, 29.43 mmol) in acetic acid (91.90 g, 1.53 mol, 87.61 mL), was added sulfuric acid (2.89 g, 29.43 mmol, 1.58 mL). The resulting mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine solution (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (Silica gel, 230-400 mesh) eluted with 45-55% ethyl acetate in petroleum ether to give 3-(6- bromo-1-methyl-indazol-3-yl)-3-methyl-piperidine-2,6-dione (B-40, 8.5 g, 24.18 mmol, 82.2% yield, 95.63% purity) as a yellow solid. LCMS (ESI): m/z 336.2 [M+H]⁺; room temperature-0.92 min. ¹H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1H), 7.98 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H), 2.60-2.54 (m, 2H), 2.45-2.39 (m, 1H), 2.17-2.10 (m, 1H), 1.65 (s, 3H) ppm. Step 9: To a solution of 3-(6-bromo-1-methyl-indazol-3-yl)-3-methyl-piperidine-2,6-dione (B- 40; 1 g, 2.97 mmol) in 1,4-dioxane (20 mL), was added cesium fluoride (677.76 mg, 4.46 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (12; 1.38 g, 4.46 mmol) and [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (291.48 mg, 356.95 μmol). The resulting mixture was heated at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by flash chromatography (Silica gel, 230-400 mesh) eluted with 40-45% ethyl acetate in petroleum ether to give tert-butyl 4-[1-methyl-3-(3-methyl-2,6-dioxo-3-piperidyl)indazol-6-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (13, 0.6 g, 1.20 mmol, 40.2% yield, 87.34% purity) as an off-white solid. UPLC (ESI): m/z 439.8 [M+H]⁺; room temperature-0.98 min. Step 10: To a solution of tert-butyl 4-[1-methyl-3-(3-methyl-2,6-dioxo-3-piperidyl)indazol-6-yl]- 3,6-dihydro-2H-pyridine-1-carboxylate (13, 0.6 g, 1.20 mmol) in ethyl acetate (30 mL), was added 10% palladium on carbon (dry basis, 239.92 mg, 2.03 mmol). The resulting suspension was stirred at room temperature under a hydrogen atmosphere (~1 kg/cm²) for 18 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase chromatography foll i h d di f ld ( P C18); Mobile phase A: 0.1% HCOOH in water and B: acetonitrile; Flow rate: 10 mL/minute. The fractions containing the product were combined and lyophilized to give tert-butyl 4-[1-methyl-3-(3-methyl-2,6- dioxo-3-piperidyl)indazol-6-yl]piperidine-1-carboxylate (B-41, 0.41 g, 928.46 μmol, 77.7% yield, 99.76% purity) as an off-white solid. LCMS (ESI): m/z 441.3 [M+H]⁺; room temperature- 2.98 min. ¹H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.04 (dd, J = 8.4, 0.8 Hz, 1H), 4.13-4.10 (m, 2H), 3.96 (s, 3H), 2.85-2.79 (m, 3H), 2.60- 2.56 (m, 2H), 2.42-2.33 (m, 1H), 2.15-2.08 (m, 1H), 1.82-1.79 (m, 2H), 1.64 (s, 3H), 1.62-1.55 (m, 2H), 1.43 (s, 9H) ppm. Step 11: To a solution of tert-butyl 4-[1-methyl-3-(3-methyl-2,6-dioxo-3-piperidyl)indazol-6- yl]piperidine-1-carboxylate (B-41; 0.7 g, 1.52 mmol) in dichloromethane (5 mL), cooled to 0 °C, was added hydrogen chloride solution (4 M in 1,4-dioxane, 4.00 g, 109.71 mmol, 5 mL). The resulting mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure to give the residue which was triturated with methyl tert- butyl ether (3 x 50 mL) to give 3-methyl-3-[1-methyl-6-(4-piperidyl)indazol-3-yl]piperidine- 2,6-dione hydrochloride (B-42; 0.55 g, 1.40 mmol, 92.2% yield, 95.90% purity) as an off-white solid. LCMS (ESI): m/z 341.2 [M+H]⁺; room temperature-0.45 min. ¹H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 8.94 (d, J = 9.2 Hz, 1H), 8.71 (d, J = 10.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.03 (dd, J = 8.4, 0.8 Hz, 1H), 3.98 (s, 3H), 3.40 (br s, 2H), 3.07-2.96 (m, 3H), 2.61-2.56 (m, 2H), 2.43-2.34 (m, 1H), 2.16-2.12 (m, 1H), 2.01-1.90 (m, 4H), 1.65 (s, 3H) ppm. Synthesis B33: Synthesis of 3-(6-(piperidin-4-yl)benzo[d]isoxazol-3-yl)piperidine-2,6-dione (B-44)

Step-1: To a stirred solution of 1-(4-bromo-2-hydroxyphenyl)ethan-1-one (1) (90.0 g, 419 mmol) in toluene (900 mL), sodium hydride, 60% dispersion in mineral oil (100 g, 2.51 mol) and diethyl carbonate (2) (198 g, 1.67 mol) were added at 0 °C. The reaction mixture was stirred at 110 °C for 2 hours under nitrogen atmosphere. Upon completion, the reaction mixture was quenched (reverse quenching) by ice and the product was extracted with ethyl acetate (2 x 2 L). The aqueous layer was acidified (pH 3-4) with 2N HCl (500 mL), and subsequently solid precipitates were formed. The solid residue was filtered through Buchner funnel to afford 7-bromo-4- hydroxy-chromen-2-one (3) (85 g, 336 mmol, 80% yield, 95% purity) as off white solid. LCMS (ES-): m/z 238.94 [M-H]-. Step-2: To a solution of 7-bromo-4-hydroxy-2H-chromen-2-one (3) (90.0 g, 373 mmol) in ethanol (900 mL) were added NaOAc (91.9 g, 1.12 mol) and hydroxylamine hydrochloride (51.9 g, 747 mmol). The reaction mixture was stirred at 80 °C for 4 hours, while monitoring the progress by TLC and LCMS. Upon completion, the reaction mixture was evaporated under reduced pressure and the crude was diluted with water and acidified (pH 3-4) with 2N HCl (500 mL). Subsequently solid precipitates formed, and these were filtered off through Buchner funnel. The residue was dried to afford 2-(6-bromobenzo[d]isoxazol-3-yl) acetic acid (4) (78.0 g, 256 mmol, 69% yield, 84% purity) as brown solid. LCMS (ES⁺): m/z 255.96 [M+H]⁺. Step-3: To a stirred solution 2-(6-bromobenzo[d]isoxazol-3-yl) acetic acid (4) (80.0 g, 312 mmol) in ethanol (800 mL) was added H2SO4 (33.2 mL, 625 mmol). The reaction mixture was stirred at 80 °C for two hours. and the progress was monitored by LCMS and TLC. Upon completion, the reaction mixture was concentrated under reduced pressure and the obtained crude was quenched with saturated sodium bicarbonate solution (500 ml). Subsequently the product was extracted with ethyl acetate (2 x 2 L). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford ethyl 2-(6- bromobenzo[d]isoxazol-3-yl) acetate (5) (65.0 g, 189 mmol, 61% yield, 83% purity) as brown liquid. LCMS (ES⁺): m/z 284.24 [M+H]⁺ Step-4: To a stirred solution of ethyl 2-(6-bromobenzo[d]isoxazol-3-yl)acetate (5) (65 g, 229 mmol) in THF (2.0 L) were added prop-2-enamide (6) (16.3 g, 229 mmol) at 0 °C and potassium tert-butoxide (25.7 g, 229 mmol). The resulting mixture was stirred at 0 °C for 2 hours, while monitoring the progress by TLC and LCMS. On completion, the reaction mixture was quenched with cold water (2 L) and extracted with ethyl acetate (2 x 2 L). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude was washed with n-pentane to afford the desired product 3-(6-bromo-1,2-benzoxazol-3- yl)piperidine-2,6-dione (7) (33.0 g, 80.9 mmol, 35% yield, 76% purity) as brown solid. LCMS (ES-): m/z 307.21 [M-H]-. Step-5: To a stirred solution of 3-(6-bromobenzo[d]isoxazol-3-yl)piperidine-2,6-dione (7) (31.0 g, 100 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylate (8) (37.2 g, 120 mmol) in 1,4-dioxane (240 mL) and water (60 mL) was added triethylamine (30.4 g, 301 mmol, 41.9 mL) at room temperature. The resultant mixture was purged with argon gas for 10 minutes and subsequently Pd(dppf)Cl2. DCM (8.18 g, 10.0 mmol) was added. The resulting suspension was stirred at 80 °C for 3 hours. Upon completion, the reaction mixture was diluted with water (1 L) and the product was extracted with ethyl acetate (5 L X 2). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure and the crude was purified by column chromatography using (100-200 mesh) silica gel and 0-100% ethyl acetate in petroleum ether as eluent to afford tert-butyl 4-(3-(2,6- dioxopiperidin-3-yl)benzo[d]isoxazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9) (20.0 g, 43.6 mmol, 43% yield, 90% purity) as white solid. LCMS (ES-): m/z 410.22 [M-H]-. Step-6: To a stirred solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-6-yl)- 3,6-dihydropyridine-1(2H)-carboxylate (9) (1.0 g, 2.43 mmol) in ethyl acetate (200 mL) was added 10% palladium on carbon, 50% wet basis (0.6 g, 3.38 mmol). The resulting suspension was stirred at room temperature under H₂ (10 Psi, Parr shaker) for 3 hours. Upon completion, the reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude was triturated with Et₂O (20 mL) to afford tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-6-yl)piperidine-1-carboxylate (B-43) (0.6 g, 1.41 mmol, i ld i ) hi lid ( ): m/z 412.43 [M-H]-. Step-7: To a solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-6- yl)piperidine-1-carboxylate (B-43) (0.5 g, 1.21 mmol ) in 1,4-dioxane (5 mL) was added hydrogen chloride (4M in 1,4-dioxane, 99%, 5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to afford the crude product which was triturated with diethyl ether to afford 3-(6-(piperidin-4-yl)benzo[d]isoxazol-3-yl)piperidine- 2,6-dione (B-44) (0.4 g, 1.04 mmol, 85.86% yield, 90.80% purity) as an off-white solid. LCMS (ESI⁺): m/z 314.43 [M+H]⁺. Synthesis B34: Synthesis of 3-[7-(4-piperidyl)-1,2-benzoxazol-3-yl]piperidine-2,6-dione (B- 46) Step-1: To a stirred solution of 1-(2-bromo-6-hydroxy-phenyl)ethanone (1) (50 g, 233 mmol) in toluene (500 mL), di h d id di i i i l il ( 8 g, 1.40 mol) and diethyl carbonate 2 (110 g, 930 mmol) were added at 0 °C. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen atmosphere. Upon completion, the reaction mixture was quenched (reverse quenching) by ice water (2 L) and extracted with ethyl acetate (2 x 2 L). The aqueous layer was acidified (pH 3-4) with 2N HCl (500 mL). Subsequently solid precipitates form and these residues were filtered through Buchner funnel to afford 8-bromo-4-hydroxy-chromen-2- one 3 (48 g, 165 mmol, 71% yield, 83% purity) as off-white solid. LCMS (ES⁺): m/z 241.01 [M+H]⁺. Step-2: To a solution of 8-bromo-4-hydroxy-chromen-2-one (3) (70 g, 290 mmol) in ethanol (722 mL) were added sodium acetate (71.5 g, 871 mmol) and hydroxylamine hydrochloride (40.4 g, 581 mmol). The reaction mixture was stirred at 80 °C for 4 hours, while monitoring the progress by TLC and LCMS. Upon completion, the reaction mixture was evaporated under reduced pressure and the crude was diluted with water and acidified (pH 3-4) with 2N HCl (500 mL). Subsequently solid precipitates formed, and these were filtered off through Buchner funnel. The residue was dried to afford 2-(7-bromo-1,2-benzoxazol-3-yl) acetic acid (4) (67 g, 230 mmol, 79% yield, 88% purity) LCMS (ES⁺): m/z 256.21 [M+H]⁺. Step-3: To a stirred solution of 2-(7-bromo-1,2-benzoxazol-3-yl)acetic acid (4) (66 g, 258 mmol) in ethanol (660 mL) was added H₂SO₄ (27.6 mL, 516 mmol). The resultant reaction mixture was heated at 80 °C for 4 hours. Upon completion, the reaction mixture was concentrated under reduced pressure and the obtained crude was quenched with saturated sodium bicarbonate solution (500 mL). Subsequently the product was extracted with ethyl acetate (2 x 2 L). The combined organic layers was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product ethyl 2-(6-bromo-1,2-benzoxazol-3-yl)acetate 5 (65.0 g, 189 mmol, 61% yield, 83% purity) as brown liquid. LCMS (ES⁺): m/z 284.16 [M+H]⁺. Step-4: To a stirred solution of ethyl 2-(7-bromo-1,2-benzoxazol-3-yl)acetate (5) (48 g, 169 mmol) in tetrahydrofuran (2.0 L) were added prop-2-enamide (6) (12.0 g, 169 mmol) at 0 °C and potassium tert-butoxide (19.0 g, 169 mmol). The reaction mixture was stirred at 0 °C for 1 hour, while monitoring the progress by TLC and LCMS. On completion, the reaction mixture was quenched with cold water (2 L) and extracted with ethyl acetate (2 x 2 L). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The obtained crude was washed with n-pentane to afford the desired product 3-(7-bromo-1,2- benzoxazol-3-yl)piperidine-2,6-dione (7) (27 g, 74.6 mmol, 44% yield, 85% purity). LCMS (ES⁺): m/z 309.20 [M+H]⁺ Step-5: To a stirred solution of 3-(7-bromo-1,2-benzoxazol-3-yl)piperidine-2,6-dione (7) (27 g, 87.4 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylate (8) (32.4 g, 105 mmol) in dioxane (250 mL) and water (30 mL) was added triethylamine (26.5 g, 262 mmol) at room temperature. The resultant mixture was purged with argon gas for 10 minutes and subsequently Pd(dppf)Cl₂·DCM (7.13 g, 8.73 mmol) was added. The resulting suspension was stirred at 80 °C for 3 hours. Upon completion, the reaction mixture was diluted with water (1 L) and the product was extracted with ethyl acetate (5 L x 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure and the obtained crude was purified by column chromatography using (100-200 mesh) silica gel and 0-100% ethyl acetate in petroleum ether as eluent to afford the desired product tert- butyl 4-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-7-yl]-3,6-dihydro-2H-pyridine-1- carboxylate (9) (17.2 g, 37.8 mmol, 43% yield, 90% purity). LCMS (ES-): m/z 410.43 [M-H]- Step-6: To a stirred solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-7-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (9) (4 g, 9.72 mmol) in ethyl acetate (800 mL) was added 10% palladium on carbon, 50% wet basis (2.4 g, 9.72 mmol). The resulting suspension was stirred at room temperature under H2 (10 psi, Parr shaker) for 3 hours. Upon completion, the reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude was triturated with Et2O (20 mL) to afford the desired product tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-7-yl]piperidine-1- carboxylate (B-45) (2.5 g, 5.94 mmol, 61% yield, 98% purity) as white solid. LCMS (ES-): m/z 412.47 [M-H]- Step-7: To a solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-7-yl]piperidine- 1-carboxylate (B-45) (0.5 g, 1.21 mmol, no salt) in 1,4-dioxane (5 mL) was added hydrogen chloride, (4M in 1,4-dioxane, 99%, 5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure to afford the crude product which was triturated with diethyl ether to afford 3-[7-(4-piperidyl)-1,2-benzoxazol-3-yl]piperidine-2,6- dione (B-46) (0.4 g, 1.06 mmol, 87.59% yield, 92.63% purity, hydrochloric acid) as an off-white solid. LCMS (ESI) / 1-(6-(piperidin-4-yl)benzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (B-47) Compound 1-(6-(piperidin-4-yl)benzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)- dione was prepared using the method described on page 194-197 of WO2022235945 A1. 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione (B-48) Compound 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione was prepared using was prepared using the method described on page 68-70 of WO2023283372 A1. 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (B-49) Compound 1-(4-(piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione was prepared using was prepared using the method described on page 168-170 of WO2022235945 A1. N-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-yl)benzamide (B-50) Compound N-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-yl)benzamide was prepared using was prepared using the method described on page 227 of WO2023055952 A1. Synthesis B35: Synthesis of 3-(4-(piperidin-4-yl)benzyl)piperidine-2,6-dione (B-52) O O Boc I B B N O O BnO N OBn Boc N Pd(dppf)Cl₂, KOAc Pd(PPh₃)₄, K₂CO₃ BnO N OBn dioxane PPh₃, Ag₂O, DME S^tep-3 O B _{Step-4 4} O ⁵ Step-1: Into a 250 mL round bottomed flask containing a well stirred solution of 4-(1-tert- butoxycarbonyl-4-piperidyl)benzoic acid (5 g, 16.37 mmol) in tetrahydrofuran (100 mL) at 0 °C, was added borane;tetrahydrofuran (1 M, 49.12 mL) dropwise. After 15 minutes, the ice bath was removed, and the clear solution was allowed at 25 °C for 16 hours. After completion of the reaction (TLC and UPLC), The reaction mixture was cooled in an ice bath and quenched with water (100 mL) and ethyl acetate (300 mL) was added and the mixture was washed with saturated sodium bicarbonate solution (100 mL) and brine (100 mL ). Combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give crude product, which was purified by flash silica-gel (230-400 mesh) column with 0- 100% ethyl acetate/petroleum ether. The desired compound eluted at 5-7 % to give tert-butyl 4- [4-(hydroxymethyl)phenyl]piperidine-1-carboxylate (4.5 g, 15.43 mmol, 94.24% yield, 99.92% purity, no salt) as off-white solid. LC-MS (ESI): m/z 192.2 [M-COOtBu+H]⁺. Step-2: Into a 500 mL single-neck round-bottom flask containing the solution of tert-butyl 4-[4- (hydroxymethyl)phenyl]piperidine-1-carboxylate (9 g, 30.86 mmol) in dichloromethane (180 mL) were added triphenylphosphane (12.14 g, 46.29 mmol) and carbon tetrabromide (15.35 g, 46.29 mmol, 4.49 mL) at 0 °C under nitrogen atmosphere. Then the reaction mixture was stirred at 25 °C for 1 hour. After consumption of the starting material, the reaction mixture was poured into cold water (200 mL) slowly and extracted with dichloromethane (3 x 500 mL). Organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give crude, which was purified by flash silica-gel (230-400 mesh) column with 0-100% ethyl acetate/petroleum ether while desired compound eluting at 10 % to afford tert-butyl 4-[4-(bromomethyl)phenyl]piperidine-1-carboxylate (9 g, 24.50 mmol, 79.37% yield, 96.43% purity, No Salt) as white solid. LC-MS (ESI): m/z 256.2 [M-COOtBu+H]⁺. Step-3: Into a 250 ml sealed tube containing a well-stirred solution of tert-butyl 4-[4- (bromomethyl)phenyl]piperidine-1-carboxylate (5 g, 13.61 mmol) in anhydrous 1,4 Dioxane (75 mL) was added potassium acetate (2.67 g, 27.22 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 5 minutes. Subsequently, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.18 g, 20.41 mmol) and cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (497.90 mg, 680.46 μmol) were added to the reaction mixture and reaction mixture was heated to 110 °C for 16 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered through celite bed and washed with ethyl acetate (250 mL), the combined organic phases were concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography (silica gel, 230-400 mesh) column with 0-30% ethyl acetate/petroleum ether while desired compound eluting at 5 % to give tert-butyl 4-[4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methyl]phenyl]piperidine-1-carboxylate (5.6 g, 12.65 mmol, 92.96% yield, 90.67% purity, no salt) as off-white solid. LC-MS (ESI): m/z 302.2 [M-COOtBu+H]⁺ Step-4: Into a 20 mL vial containing a well-stirred solution of tert-butyl 4-[4-[(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]phenyl]piperidine-1-carboxylate (974.24 mg, 2.20 mmol) and 2,6-dibenzyloxy-3-iodo-pyridine (900.00 mg, 1.83 mmol) in DME (10 mL), were added Potassium carbonate (380.23 mg, 2.75 mmol), disilver;oxygen(2-) (637.55 mg, 2.75 mmol, 89.29 μL) d i h l h h ( l) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 5 minutes. Subsequently, Tetrakis(triphenylphosphine)palladium(0) (211.94 mg, 183.41 μmol) was added to the reaction mixture and reaction mixture was heated to 85 °C for 16 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was cooled to room temperature and poured into water (25 mL), and extracted with ethyl acetate (2 x 50 mL ). Organic phases were combined and washed with brine (5 mL). Combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford a crude product, which was purified by flash silica-gel (230-400 mesh) column with 0-100% ethyl acetate/petroleum ether while desired compound eluting at 4 % to give tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)methyl]phenyl]piperidine-1-carboxylate (0.415 g, 655.30 μmol, 35.73% yield, 89.17% purity, no salt) as brown solid. UPLC (ESI): m/z 565.3 [M+H]⁺. Step-5: Into a 25 mL single-necked round-bottom flask containing a well-stirred suspension of tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)methyl]phenyl]piperidine-1-carboxylate (0.1 g, 157.90 μmol) in 1,4-dioxane (2 mL) and ethanol (2 mL) was added palladium, 10% on carbon, Type 487, dry (16.80 mg, 157.90 μmol) at room temperature under nitrogen atmosphere and the resulting suspension was stirred at room temperature under hydrogen atmosphere (bladder) for 16 hours. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure to afford tert-butyl 4-[4-[(2,6-dioxo-3- piperidyl)methyl]phenyl]piperidine-1-carboxylate (B-51) (0.061 g, 155.10 μmol, 98.23% yield, 98.27% purity, no salt) as white solid. LCMS (ESI): m/z 287.2 [M-COOtBu+H]⁺ Step-6: To a solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)methyl]phenyl]piperidine-1- carboxylate in dichloromethane is added 4 M HCl in dioxane (10 equiv.) and the reaction is stirred at room temperature for 16 hours. Upon completion of the reaction, the solvent is removed under reduced pressure and the crude product is purified by column chromatography to afford 3-(4-(piperidin-4-yl)benzyl)piperidine-2,6-dione (B-52). 3-(6-(aminomethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (B-53) Compound 3-(6-(aminomethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione was prepared using was prepared using the method described on page 322-324 of WO2023019166 A1. 3-(2-oxo-5-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (B-54) Compound 3-(2-oxo-5-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione was prepared using was prepared using the method described on page 335-338 of WO2023019166 A1. 3-(2-oxo-6-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (B-55)

Compound 3-(2-oxo-6-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione was prepared using the method described on page 203-205 of WO2021127586 A1. Synthesis B36: Synthesis of 3-[8-(4-piperidyl)-2,3-dihydro-1,4-benzoxazin-4-yl]piperidine- 2,6-dione (B-57) Boc Boc N N H N O H₂ / Pd-C O TFA O N Step-7 N Step-8 N BnO O O N HN HN OBn ₁₀ O B-56 ^B-57 O Step-1: To a stirred solution of 2-bromo-6-nitro-phenol 1 (50 g, 229.35 mmol) in tetrahydrofuran (200 mL) was added zinc (149.97 g, 2.29 mol, 21.00 mL) and cooled to 0 °C. Then ammonium chloride (122.68 g, 2.29 mol) was dissolved in water (100 mL) and was added dropwise to the reaction mixture and stirred for 1 hour at room temperature. Upon completion, the reaction mixture was filtered through celite bed, washed with ethyl acetate and concentrated. The crude was washed with water and extracted with ethyl acetate (3×500mL). The combined organic layers were dried and concentrated in vacuo and the crude material was triturated with pentane to afford 2-amino-6-bromo-phenol 2 (35 g, 109.31 mmol, 47.66% yield) as a black color solid. LCMS (ES⁺): m/z 188.29 [M+H]⁺. Step-2: To a stirred solution of 2-amino-6-bromo-phenol 2 (35 g, 186.15 mmol) in N,N- dimethylformamide (300 mL) was added potassium carbonate (64.32 g, 465.37 mmol). The mixture was cooled to 0 °C and 2-chloroacetyl chloride 3 (23.13 g, 204.76 mmol, 16.29 mL) was added dropwise. The reaction was stirred at room temperature overnight. After completion of the reaction, the reaction mixture poured into ice and stirred for 1 hour and filtered. Then the solid was dried under vacuum to afford the 8-bromo-4H-1,4-benzoxazin-3-one 4 (35 g, 101.74 mmol, 54.66% yield) as dark brown solid. LCMS (ES⁺): m/z 228.08 [M+H]⁺. Step-3: To a stirred solution of 8-bromo-4H-1,4-benzoxazin-3-one 4 (20 g, 87.70 mmol) in tetrahydrofuran (100 mL) at 0 °C, was added borane methyl sulfanylmethane (67.28 g, 885.68 mmol, 84.00 mL) dropwise. The reaction mixture was heated at 78 °C for an hour. Upon completion, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine solution and dried over sodium sulphate and concentrated. The crude product thus obtained was purified by column chromatography to afford 8-bromo-3,4-dihydro-2H-1,4-benzoxazine 5 (16 g, 65.92 mmol, 75.16% yield) as a white solid. LCMS (ES⁺): m/z 213.83 [M+H]⁺. Step-4: To a solution of 8-bromo-3,4-dihydro-2H-1,4-benzoxazine 5 (16 g, 74.75 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate 6 (23.11 g, 74.75 mmol) in 1,4-dioxane (80 mL) and water (10 mL) was added tripotassium phosphate (47.60 g, 224.24 mmol) at room temperature. The reaction mixture was degassed with argon purging and Pd(dppf)Cl2 (2.73 g, 3.74 mmol) was added. The reaction mixture was again degassed with argon for 5 minutes, and it was stirred at 90 °C for 16 hours. After completion of the reaction, it was concentrated under reduced pressure to afford the crude product, which was purified by column chromatography using Davisil silica and 30% ethyl acetate in petroleum ether as eluent to afford tert-butyl 4-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)- 3,6-dihydro-2H-pyridine-1-carboxylate 7 (23 g, 62.09 mmol, 83.07% yield) as colorless gum. LCMS (ES⁺): m/z 217.02 [M–Boc+H]⁺. Step-5: A solution of tert-butyl 4-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)-3,6-dihydro-2H- pyridine-1-carboxylate 7 (23 g, 66.37 mmol) in methanol (500 mL) was degassed with N2 for 10 minutes and 10% palladium on carbon (21 g, 66.37 mmol) was added. The reaction mixture was stirred for 16 hours at 25°C in par shaker under hydrogen pressure (80 psi). After completion of the reaction, it wa fil d li b d d h d ih h l etate. The volatiles were evaporated under reduced pressure to afford the crude product, which was purified by column chromatography to afford tert-butyl 4-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)piperidine-1- carboxylate 8 (22 g, 56.24 mmol, 84.73% yield). LCMS (ES⁺): m/z 263.41 [M-tBu+H]⁺. Step-6: To a solution of t-butyl 4-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)piperidine-1- carboxylate 8 (22 g, 65.95 mmol) and 2,6-dibenzyloxy-3-bromo-pyridine 9 (24.42 g, 65.95 mmol) in toluene (420 mL) was added sodium tert-butoxide (12.68 g, 131.91 mmol) at room temperature. The reaction mixture was degassed with N₂ for 10 minutes and Pd₂(dba)₃ (3.02 g, 3.30 mmol) was added. Subsequently, Xantphos (7.63 g, 13.19 mmol) was added, and the reaction mixture was degassed with N₂ for 5 minutes. The reaction mixture was stirred at 110 °C for 16 hours. After completion of the reaction, it was concentrated under reduced pressure to give the crude product, which was purified by column chromatography using Davisil silica and 10% ethyl acetate in petroleum ether as eluent to afford t-butyl 4-[4-(2,4-dibenzyloxyphenyl)- 2,3-dihydro-1,4-benzoxazin-8-yl]piperidine-1-carboxylate 10 (20 g, 26.26 mmol, 39.81% yield) as pale yellow colour gum. LCMS (ES⁺): m/z 552.47 [M-tBu+H]⁺. Step-7: A solution of tert-butyl 4-[4-(2,4-dibenzyloxyphenyl)-2,3-dihydro-1,4-benzoxazin-8- yl]piperidine-1-carboxylate 10 (20 g, 32.96 mmol) in ethanol (200 mL) and ethyl acetate (200 mL) was degassed with N₂ for 10 minutes and palladium, 10% on carbon (20 g, 32.96 mmol) was added. The reaction mixture was purged with H2 gas for 5 minutes and the stirring was continued for 24 hours at room temperature under hydrogen atmosphere (70 psi) in a Parr shaker. The progress of the reaction was monitored by TLC. After completion of the reaction, it was filtered over celite bed and washed with ethyl acetate and 10% methanol in dichloromethane. The volatiles were removed under reduced pressure to afford the crude product, which was purified by column chromatography over Davisil silica, using 50% ethyl acetate in petroleum ether as eluent to afford tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)-2,3-dihydro-1,4-benzoxazin-8- yl]piperidine-1-carboxylate B-56 (7 g, 15.13 mmol, 45.90% yield) as red solid. LCMS (ES⁺): m/z 430.32 [M+H]⁺. Step-8: To a stirred solution of t-butyl 4-[4-(2,6-dioxo-3-piperidyl)-2,3-dihydro-1,4-benzoxazin- 8-yl]piperidine-1-carboxylate B-56 (7 g, 16.30 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (14.80 g, 129.80 mmol, 10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, the solvents were removed under reduced pres h d d b i d h d i h diethyl ether and dried to afford 3-[8-(4-piperidyl)-2,3-dihydro-1,4-benzoxazin-4-yl]piperidine-2,6-dione B-57 (7 g, 14.13 mmol, 86.67% yield, TFA salt). LCMS (ES⁺): m/z 330.27 [M+H]⁺. Synthesis B37: Synthesis of 3-[5-(4-piperidyl)-3,4-dihydro-2H-quinolin-1-yl]piperidine- 2,6-dione (B-59) Step-1: A mixture of 5-bromo-1,2,3,4-tetrahydroquinoline 1 (2 g, 9.43 mmol, 1.0 eq.) and tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate 2 (3.50 g, 11.32 mmol, 1.2 eq.) in 1,4-dioxane (40 mL) was degassed with nitrogen for 5 minutes. To the reaction mixture, tripotassium;phosphate (6.01 g, 28.29 mmol,3.0 eq.) in water (10 mL)) was added and the mixture was degassed for an additional 5 minutes. Then cyclopentyl(diphenyl) phosphane;dichloromethane;dichloropalladium;iron (770.10 mg, 943.01 μmol,0.1 eq.) was added and the reaction mixture was heated at 95 °C for 16 hours. Upon completion of the reaction, it was cooled to room temperature, filtered through celite bed, and washed with ethyl acetate. The filtrate was washed with water and brine solution, dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum to obtain the crude material, which was purified by column chromatography (Davisil Silica, elution solvent 0-30% ethyl acetate in n-hexane) to afford tert-butyl 4-(1,2,3,4-tetrahydroquinolin-5-yl)-3,6-dihydro-2H-pyridine-1- carboxylate 3 (2.2 g, 6.91 mmol, 73.31% yield) as an off white solid. LCMS (ES⁺): m/z 315.34 [M+H]⁺. Step-2: A solution of tert-butyl 4-(1,2,3,4-tetrahydroquinolin-5-yl)-3,6-dihydro-2H-pyridine-1- carboxylate 3 (2.2 g, 7.00 mmol,1.0 eq.) in Methanol (50 mL) was degassed with nitrogen gas for 15 minutes in a 250 mL Parr Shaker vessel Subsequently 10% palladium on carbon (2.23 g, 20.99 mmol,3.0 eq.) was added to the reaction mixture and the reaction mixture was stirred under hydrogen atmosphere for 16 hours at 25 °C at 70 Psi. Upon completion of the reaction, it was filtered through celite bed, and washed with methanol. The filtrate was evaporated under vacuum to afford the crude residue, which was purified by column chromatography (Davisil silica, 0-50% ethyl acetate in petroleum ether) to afford t-butyl 4-(1, 2, 3, 4-tetrahydroquinolin- 5-yl)-piperidine-1-carboxylate 4 (1.8 g, 5.40 mmol, 77.23% yield) as a white solid. LCMS (ES⁺): m/z 261.57 [M–tBu+H]⁺. Step-3: To a solution of tert-butyl 4-(1,2,3,4-tetrahydroquinolin-5-yl)piperidine-1-carboxylate 4 (1 g, 3.16 mmol, 1.0 eq.) and 3-bromopiperidine-2,6-dione 5 (1.82 g, 9.48 mmol,3.0 eq.) in N,N- dimethylformamide (10 mL), sodium bicarbonate (2.65 g, 31.60 mmol, 1.23 mL,10.0 eq.) was added under nitrogen atmosphere. The reaction mixture was heated at 80 °C for 16 hours. Then the reaction mixture was cooled to room temperature and was diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and evaporated under vacuum to afford the crude compound which was purified by column chromatography (Davisil Silica, 0-50% ethyl acetate in petroleum ether) to afford tert-butyl 4-[1-(2,6-dioxo-3- piperidyl)-3,4-dihydro-2H-quinolin-5-yl]piperidine-1-carboxylate B-58 (500 mg, 1.13 mmol, 35.90% yield) as a light green solid. LCMS (ES⁺): m/z 428.78[M+H]⁺. Step-4: To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert- butyl 4-[1-(2,6-dioxo-3-piperidyl)-3,4-dihydro-2H-quinolin-5-yl]piperidine-1-carboxylate B-58 (1.1 g, 2.57 mmol) in anhydrous dichloromethane (5 mL) was added 4 M HCl in dioxane (6.43 mL) at ambient temperature. The resulting mixture was stirred at room temperature for two hours. Upon completion of the reaction, excess solvents were removed from the reaction mixture under reduced pressure and the crude product was washed with hexane (50 mL) to afford 3-[5- (4-piperidyl)-3,4-dihydro-2H-quinolin-1-yl]piperidine-2,6-dione B-59 (900 mg, 2.45 mmol, 95.07% yield, HCl salt) as an off-white solid. LCMS (ESI): m/z 328 [M+H]⁺. Synthesis B38: Synthesis of 3-[4-(4-piperidyl)indolin-1-yl]piperidine-2,6-dione (B-61) Step-1: To a stirred solution of 4-bromoindoline 1 (5 g, 25.24 mmol) and tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate 2 (8.59 g, 27.77 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was added tripotassium phosphate (16.08 g, 75.73 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1.03 g, 1.26 mmol). The reaction mixture was stirred at 100 °C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain crude, which was partitioned in water (100 mL) and dichloromethane (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude was purified by column chromatography (silica gel, 60-120 mesh) using 0-100% ethyl acetate in petroleum ether as eluent to afford tert-butyl 4-indolin-4-yl-3,6- dihydro-2H-pyridine-1-carboxylate 3 (4.2 g, 13.39 mmol, 53.03% yield) as a brown sticky gum. LCMS (ES⁺): m/z 301.4 [M+H]⁺. Step-2: To a stirred solution of tert-butyl 4-indolin-4-yl-3,6-dihydro-2H-pyridine-1-carboxylate 3 (100 mg, 332.90 μmol) in 1,4-dioxane (25 mL) were added AcOH (0.5 mL) and 10% Pd/C (70.85 mg, 665.79 l) d i here. The reaction mixture was stirred at room temperature under hydrogen (bladder pressure) at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered through celite bed and washed with dichloromethane (100 mL). The resulting filtrate was concentrated under reduced pressure and dried to afford tert-butyl 4-indolin-4-ylpiperidine-1-carboxylate 4 (70 mg, 192.12 μmol, 57.71% yield) as an off-white solid. LCMS (ES⁺): m/z 247.2 [M-tBu+H]⁺. Step-3: To a stirred solution of tert-butyl 4-indolin-4-ylpiperidine-1-carboxylate 4 (1 g, 3.10 mmol) in N,N-dimethylformamide (10 mL) were added sodium bicarbonate (781.29 mg, 9.30 mmol) and 3-bromopiperidine-2,6-dione 5 (892.88 mg, 4.65 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude was dissolved in dichloromethane (50 mL) and washed with water (2 × 50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude. The crude was purified by column chromatography (silica gel, 230-400 mesh) using 80% ethyl acetate in petroleum ether as eluent to afford tert- butyl 4-[1-(2,6-dioxo-3-piperidyl)indolin-4-yl]piperidine-1-carboxylate (B-60) (650 mg) as a brown solid. Step-4: To a single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1- (2,6-dioxo-3-piperidyl)indolin-4-yl]piperidine-1-carboxylate (400 mg, 967.33 μmol) in dichloromethane (5 mL) was added 4.0 M hydrogen chloride solution in dioxane (5.00 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 hour. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was washed with MTBE (3 × 15 mL), and dried under reduced pressure to afford 3-[4-(4-piperidyl)indolin-1-yl]piperidine-2,6-dione (B-61) (338 mg, 959.93 μmol, 99.24% yield, HCl salt) as a brown solid. LCMS (ES⁺): m/z 314.3 [M+H]⁺. Synthesis B39: Synthesis of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (B- 62-SM)

Step-1: To a stirred solution of 7-bromo-1H-indazole (1) (1 g, 5.08 mmol) in N,N- dimethylformamide (10 mL) was added potassium hydroxide (0.569 g, 10.15 mmol) portion wise at 0 °C then added molecular iodine (1.42 g, 5.58 mmol) under nitrogen atmosphere. The reaction mixture was stirred for 16 hours at 25 °C. After complete consumption of starting material, the reaction mixture was concentrated under vacuum. It was stirred with ethyl acetate (50 mL) and water (100 mL) then separated organic layer then concentrated. That crude was stirred with n-pentane (50 mL) for 15 minutes and filtered to afford 7-bromo-3-iodo-1H-indazole (2) (1 g, 3.03 mmol, 59.63% yield, 97.73% purity) as off white solid. ¹H-NMR (400 MHz, DMSO-d6) δ 7.615 (dd, J = 7.8 Hz, 0.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H). Step-2: To a stirred solution of 7-bromo-3-iodo-1H-indazole (2) (65 g, 201.28 mmol) in acetone (650 mL), was added potassium hydroxide (22.59 g, 402.57 mmol, 11.05 mL) portion wise at 0 °C then added methyl iodide (31.43 g, 221.41 mmol, 13.78 mL) under nitrogen atmosphere. The reaction mixture was stirred for 16 hours at 25 °C. After complete consumption of starting materials, the reaction mixture was concentrated under vacuum. It was stirred with ethyl acetate (1500 mL) and water (1000 mL) then separated organic layer dried over anhydrous sodium sulphate, concentrated under reduced pressure to obtain the crude. The crude was stirred with n- pentane (500 mL) for 15 minutes and filtered to afford 7-bromo-3-iodo-1-methyl-indazole (3) (40 g, 117.31 mmol, 58.28% yield, 98.82% purity) as off white solid. LCMS (ESI): m/z 337.15 [M+H]⁺. Step-3: To a stirred solution of 7-bromo-3-iodo-1-methyl-indazole (3) (6 g, 17.81 mmol) in water (15 mL) and dioxane (80 mL)was added 26 dibenzyloxy 3 (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (4) (7.43 g, 17.81 mmol, no salt) and potassium carbonate (7.38 g, 53.42 mmol) at room temperature, then the reaction mixture was purged with nitrogen for 10 minutes. Then Pd(dppf)Cl2·CH2Cl2 (0.727 g, 0.890 μmol) was added and purged with nitrogen for 10 minutes. Then the reaction mixture was stirred at 60 °C for 16 hours. After completion of reaction, the reaction was filtered and evaporated to obtain the crude. The crude was purified using silica (200-400 mesh) and eluted with 2% ethyl acetate in petroleum ether to obtain 7- bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (B-62-SM) (3 g, 4.44 mmol, 24.92% yield, 74% purity) as white solid. LCMS(ES+): m/z 500.47 [M+H]⁺. Synthesis B40: Synthesis of 3- [6-(3-azaspiro [5.5] undecan-9-yl)-1-methyl-indazol-3-yl] piperidine-2,6-dione (B-62)

Step-1: To a stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1) (1 g, 2.00 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (2) (659.73 mg, 2.60 mmol) in dioxane (20 mL) was added potassium acetate (588.40 mg, 6.00 mmol, 374.78 μL) and degassed with nitrogen for 10 minutes, Pd(dppf)Cl₂·CH₂Cl₂ (81.60 mg, 99.92 μmol) was added, the reaction mixture again degassed for 5 minutes, the resulting reaction mixture was stirred for 16 hours at 90 °C. After complete consumption of starting materials, reaction mixture was filtered through celite bed, the filtrate was concentrated under reduced pressure to afford crude compound, which was purified column chromatography using (Davisil silica) eluted at 10 % ethyl acetate in petroleum ether to afford 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indazole (3) (0.55 g, 616.26 μmol, 30.84% yield) as a Pale yellow solid. LCMS (ESI): m/z 548.67 [M+H]⁺. Step-2a: To a stirred solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (4a) (2 g, 7.48 mmol) in tetrahydrofuran (4.26 mL) was added dropwise a solution of lithium bis(trimethylsilyl)amide (2 M, 7.48 mL) and stirred at -78 ⁰C after the addition was complete, the reaction mixture was stirred for 1 hour at -78 ⁰C. After 1 hour, 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (4b) (2.67 g, 7.48 mmol) was dissolved in 5 mL of tetrahydrofuran and added dropwise into the reaction solution, and stirred at -78 ⁰C for 1 hour. The mixture was warmed to 25 °C and stirred for 6 hours. Then the reaction mixture was treated with ammonium chloride solution (30 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated to give a residue, which was purified by Davisil silica gel column chromatography eluted at 10% ethyl acetate in petroleum ether to afford tert-butyl 9-(trifluoromethylsulfonyloxy)-3- azaspiro[5.5]undec-9-ene-3-carboxylate (4) (2 g, 4.61 mmol, 61.58% yield) as a brown oil. ¹H NMR (400 MHz, CDCl3) δ- 5.68 (t, J = 4.4 Hz, 1H), 3.46 (m, 2H), 3.31 (m, 2H), 2.33 (m, 2H), 2.03(m, 2H), 1.66 (m, 2H), 1.45 (s, 9 H), 1.42 (m, 4H) Step-2: To a stirred solution of 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)indazole (3) (0.85 g, 1.55 mmol) and tert-butyl 9- (trifluoromethylsulfonyloxy)-3-azaspiro[5.5]undec-9-ene-3-carboxylate (4) (775.21 mg, 1.94 mmol) in dioxane (15 mL) were added potassium carbonate (643.76 mg, 4.66 mmol) and degassed with nitr f i d(d f) l l ( mg, 155.27 μmol) was added and the resulting reaction mixture was stirred for 4 hours at 100 °C. After complete consumption of starting material, reaction mixture was filtered through on celite bed, the filtrate was concentrated under reduced pressure to afford crude compound, which was purified by column chromatography using (Davisil silica) eluted at 10 % ethyl acetate in petroleum ether to afford tert-butyl 9-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-3-azaspiro [5.5] undec-9-ene-3-carboxylate (5) (0.6 g, 647.46 μmol, 41.70% yield, 72.39% purity, no salt) as a colorless oil. LCMS (ESI): m/z 671.80 [M+1]⁺, Step-3: The stirred solution of tert-butyl 9-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6- yl]-3-azaspiro [5.5] undec-9-ene-3-carboxylate (5) (0.55 g, 819.87 μmol, no salt) in ethyl acetate (15 mL) and tetrahydrofuran (15 mL) was degassed with nitrogen for 10 minutes, then palladium, 10% on carbon, Type 487, dry (523.50 mg, 4.92 mmol) was added at room temperature. The reaction mixture was stirred under hydrogen atmosphere (20 psi) using bladder for 16 hours. After complete consumption of starting material, the reaction mixture was filtered through celite bed and washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 9-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-3- azaspiro [5.5] undecane-3-carboxylate (6) (0.3 g, 484.91 μmol, 59.15% yield) as an off-white solid. LCMS (ES+): m/z 495.45 [M+H]⁺. Step-4: To the stirred solution of tert-butyl 9-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]- 3-azaspiro [5.5] undecane-3-carboxylate (6) (100 mg, 202.17 μmol, no salt) in dichloromethane (1 mL) was added HCl in 1,4-dioxane (4 M, 1 mL) at 0 °C and the resulting reaction mixture was stirred for 1 hour at 25 °C. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain crude compound which was triturated with diethyl ether (5 mL) to afford 3- [6-(3-azaspiro [5.5] undecan-9-yl)-1-methyl-indazol-3-yl] piperidine-2,6-dione B-62 (60 mg, 113.13 μmol, 55.96% yield ) as an off-white solid. LCMS (ES⁺): m/z 395.55 [M+H]⁺. The following CRBN binders were prepared substantially following the method described above, using the corresponding starting material 1 and reactant 4. Starting material Reactant 4 in CRBN binder CRBN 1 in Step-1 Step-2 binder MS LCMS (ES⁺): m/z 396.48 [M+H]⁺ B-63 LCMS (ES⁺): m/z 370.36 [M+H]⁺ B-64 O LCMS (ES⁺): N N NH m/z 395.57 O HN [M+H]⁺ B-65 LCMS (ES⁺): m/z 396.66 [M+H]⁺ B-66 The following CRBN binders are prepared substantially following the method described above, using the corresponding starting material 1 and reactant 4. Starting material Reactant 4 in CRBN binder 1 in Step-1 Step-2 B-67 B-68 B-69 Synthesis B41: Synthesis of 3-[5-(3-azaspiro[5.5]undecan-9-yl)-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (B-70)

Step-1: To a solution of tert-butyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- azaspiro[5.5]undec-9-ene-3-carboxylate (749.84 mg, 1.99 mmol) and 5-bromo-1-(2,6- dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (855.15 mg, 1.66 mmol) in water (5 mL) and dioxane (20 mL) was added sodium carbonate (526.57 mg, 4.97 mmol) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 minutes and Pd(dppf)Cl2 (121.17 mg, 165.60 μmol) was added. The reaction mixture was degassed with nitrogen gas for an additional 5 minutes and stirred at 90 °C for 16 hours. After completion, the reaction mixture was filtered through celite bed and washed with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine solution (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the crude product. The crude was purified by column chromatography (using Davisil silica gel and 45% of ethyl acetate in petroleum ether as eluent) to afford tert-butyl 9-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)-3-azaspiro[5.5]undec-8-ene-3-carboxylate (600 mg, 30.86% yield, 67.87 % purity) as off-white solid.  LCMS (ESI): m/z 687.52 [M+H]⁺ Step-2: To a stirred solution of tert-butyl 9-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-5-yl]-3-azaspiro[5.5]undec-9-ene-3-carboxylate (0.66 g, 960.93 μmol) in ethanol (5 mL), tetrahydrofuran (5 mL), ethyl acetate (5 mL) was added 10% palladium on carbon (wetted with ca.55% water) (711.23 mg, 6.68 mmol) at 0 °C and the reaction mixture was stirred at 25 °C under hydrogen atm for 16 hours. After complete consumption of the starting material, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate (30 mL). The combined organic layers were concentrated under reduced pressure and purified using Davisil silica and 50% ethyl acetate in petroleum ether as eluent to afford tert-butyl 9-[1-(2,6- dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3-azaspiro[5.5]undecane-3-carboxylate (0.38 g, 675.80 μmol, 70.33% yield, 90.81% purity) as grey solid. LCMS (ESI): m/z 509.40 [M- H]- Step-3: To a stirred solution of tert-butyl 9-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-3-azaspiro[5.5]undecane-3-carboxylate (75 mg, 146.88 μmol, No Salt) in dichloromethane (1 mL) was added 4.0 M HCl in 1,4-dioxane (0.5 mL) by dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for an hour. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure to afford crude, which was triturated with diethyl ether (2 mL x 2) to afford 3-[5-(3-azaspiro[5.5]undecan-9-yl)-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (B-70) (65 mg, 132.39 μmol, 90.14% yield, 91.04% purity, hydrochloric acid) as an off-white solid. LCMS (ESI): m/z 411.31 [M+H]⁺. Synthesis B42: Synthesis of 3-[5-(2,7-diazaspiro[3.5]nonan-2-yl)-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (B-71) Step-1: To a solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one 1 (0.8 g, 1.55 mmol, No Salt) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate 2 (420.74 mg, 1.86 mmol) in toluene (20 mL) was added sodium t-butoxide (446.64 mg, 4.65 mmol, 435.75 μL) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 minutes and tBuXPhos Pd G3 (123.07 mg, 154.92 μmol) was added. The reaction mixture was degassed with nitrogen gas for an additional 5 minutes and stirred at 100 °C for 16 hours. The reaction was monitored by TLC and LCMS After completion of reaction, the reaction mixture was filtered through celite bed and washed with ethyl acetate (3 x 50 mL). The organic layer was washed with water (2 x 20 mL) and brine solution (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product. The crude was purified by using Davisil silica gel column chromatography using 30% of ethyl acetate in petroleum ether to afford tert-butyl 2-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-2,7- diazaspiro[3.5]nonane-7-carboxylate 3 (470 mg, 703.38 μmol, 45.40% yield, 99.04% purity, no salt) as off-white solid. LCMS (ESI): m/z 662.64 [M+H]⁺. Step-2: To a stirred solution of tert-butyl 2-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 3 (0.47 g, 710.20 μmol) in ethanol (5 mL), tetrahydrofuran (5 mL), ethyl acetate (5 mL) was added Pd/C (10% on carbon (wetted with ca.55% water)) (500 mg, 4.70 mmol) at 0 °C and stirred reaction mixture at 25 °C under hydrogen bladder atm for 16 hours. After completion of starting material, The reaction mixture was filtered through celite bed and washed with ethyl acetate (30 mL), concentrated under reduced pressure to afford crude, was purified using Davisil silica in 50% ethyl acetate in petroleum ether to afford tert-butyl 2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 4 (60 mg, 101.47 μmol, 14.29% yield, 81.78% purity, no salt) as grey solid. LCMS (ESI): m/z 484.31 [M+H]⁺. Step-3: To a stirred solution of tert-butyl 2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 4 (57 mg, 117.88 μmol) in dichloromethane (1 mL) was added HCl (4.0 M in 1,4-dioxane, 0.5 mL) at 0 °C. The reaction mixture was stirred at room temperature for two hours, while monitored by TLC. Upon completion, the reaction mixture was concentrated under reduced pressure to afford crude product. Then the crude compound was triturated with diethyl ether (2 x 20 mL) to afford 3-[5- (2,7-diazaspiro[3.5]nonan-2-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione B-71 (50 mg, 72.43 μmol, 61.45% yield, 60.83% purity, hydrochloric acid) as an off-white solid. LCMS (ES⁺): m/z 382.28 [M+H]⁺. The following CRBN binders were prepared using identical or similar methods as described above, with the corresponding starting material 1 and reactant 2. Alternative Buchwald coupling (Step-1) conditions included 1) Pd₂(dba)₃, NaOtBu, BINAP, toluene. Starting material 1 Reactant 2 in CRBN binder CRBN in Step-1 Step-1 binder MS LCMS (ES⁺): m/z 396.56 [M+H]⁺ B-72 LCMS (ES⁺): m/z 396.4 [M+H]⁺ B-73 LCMS (ES⁺): m/z 396.43 [M+H]⁺ B-74 The following CRBN binders are prepared using identical or similar methods as described above, with the corresponding starting material 1 and reactant 2. Alternative Buchwald coupling (Step-1) conditions include 1) Pd₂(dba)₃, NaOtBu, BINAP, toluene. Starting material Reactant 2 in CRBN binder CRBN 1 in Step-1 Step-1 binder MS LCMS (ES⁺) m/z 368.48 [M+H]⁺ B-75 LCMS (ESI): m/z 382.61 [M+H]⁺ B-76 Synthesis B43: Synthesis of 1-[6-(3,9-diazaspiro[5.5]undecan-3-yl)-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione (B-77) Step-1: To a stirred solution of 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4- dione (2 g, 6.19 mmol, No Salt) in N,N-dimethylformamide (30 mL) at 0 °C was added cesium carbonate (2.75 g, 15.47 mmol) followed by addition of 1-(chloromethyl)-4-methoxy-benzene (1.26 g, 8.05 mmol) The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtain crude compound. After completion of reaction, the reaction mixture was quenched with ice water to afford the solid product, which was washed with petroleum ether to afford the 1-(6-bromo-1- methyl-indazol-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (2.4 g, 4.87 mmol, 78.73% yield, 90% purity, no salt) . LCMS (ES⁺): m/z 445.58 Bromo pattern [M+2H]⁺ Step-2: To a solution of 1-(6-bromo-1-methyl-indazol-3-yl)-3-[(4- methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (1 g, 2.26 mmol, no salt) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (745.96 mg, 2.93 mmol, no salt) in 1,4-dioxane (15 mL) was added K3PO4 (1.44 g, 6.77 mmol) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 minutes and XPhos-Pd-G3 (152.76 mg, 180.47 μmol) was added. The reaction mixture was degassed with N2 gas for an additional 5 minutes and it was stirred at 100 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was filtered through celite bed and washed with ethyl acetate filtrate was concentrated in vacuo to afford the crude product , which was purified by column chromatography using 100-200 silica gel to afford tert-butyl 9-[3-[3-[(4- methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]-1-methyl-indazol-6-yl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (0.75 g, 1.05 mmol, 46.36% yield, 86% purity, no salt). LCMS [ES⁺]: m/z 617.82 [M+H]⁺. Step-3: A stirred solution of tert-butyl 9-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo- hexahydropyrimidin-1-yl]-1-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.03 g, 48.64 μmol, no salt) in dichloromethane (1 mL) was cooled to 0 °C, trifluoromethanesulfonic acid (146.00 mg, 972.84 μmol, 85.48 μL) was added and the reaction mixture was stirred for 15 minutes followed by addition of TFA (55.46 mg, 486.42 μmol, 37.22 μL) at same temperature. The reaction mixture was slowly warmed to 45 °C and continued stirring at 45°C for 16 hours. Reaction was monitored by LCMS. After completion, mixture was concentrated under reduced pressure, followed by triturating with diethyl ether (20ml*2). The mixture was stirred for two hours and then filtered to afford 1-[6-(3,9-diazaspiro[5.5]undecan- 3-yl)-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (B-77). LCMS [ES⁺]: m/z 617.75 [M+H]⁺ .

The following CRBN binder is prepared substantially following the method described above, using the corresponding starting material 1 and reactant 2. Starting material 1 Reactant 2 in CRBN binder CRBN in Step-1 Step-2 binder MS Prophetic B-78 Synthesis B44: Synthesis of 3-[4-(3-azaspiro[5.5]undecan-9-yl)anilino]piperidine-2,6-dione (B-79) Step-1: To a stirred solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1) (2 g, 7.48 mmol) in tetrahydrofuran (20 mL) was added dropwise a solution of lithium bis(trimethylsilyl)a id ( ) ⁰ d i d temperature for 1 hour. 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2) (2.67 g, 7.48 mmol) was dissolved in 5 mL of tetrahydrofuran and added to the reaction mixture dropwise, stirred at -78 ⁰C for 1.5 hours. The mixture was warmed to 25 °C and stirred for 2 hours, the reaction mixture was quenched with ammonium chloride solution (30 mL) and extracted with ethyl acetate (100 mL × 2). The organic layer and washed with brine, dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by neutral alumina column chromatography (10% ethyl acetate in petroleum ether) to give the titled compound tert-butyl 9- (trifluoromethylsulfonyloxy)-3-azaspiro[5.5]undec-9-ene-3-carboxylate (3) (1 g, 2.38 mmol, 31.80% yield, 95% purity) as a yellow oil. ¹H NMR (400 MHz, CDCl3) δ 5.68 (t, 4.4 Hz, 1H), 3.46 (m, 2H), 3.31 (m, 2H), 2.33 (m, 2H), 2.03(m, 2H), 1.66 (m, 2H), 1.45 (s, 9 H), 1.42 (m, 4H) Step-2: To a stirred solution of tert-butyl 9-(trifluoromethylsulfonyloxy)-3-azaspiro[5.5]undec- 9-ene-3-carboxylate (3) (1.5 g, 3.76 mmol) in dioxane (15 mL) were added K2CO3 (1.56 g, 11.27 mmol) and (4-nitrophenyl)boronic acid (4) (626.88 mg, 3.76 mmol) at room temperature. Then the reaction mixture was degassed with argon for 5 minutes. After that Pd(dppf)Cl2·CH2Cl2 (0.153 g, 0.187 mmol) was added to reaction mixture at room temperature and again degassed for 2 minutes. After that, the reaction mixture was stirred at 80 °C for 16 hours. Upon completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain crude. The crude was purified in silica (mesh 100-200) and eluted with 5-10% ethyl acetate in petroleum ether to afford tert-butyl 9-(4-nitrophenyl)-3-azaspiro[5.5]undec-9-ene-3-carboxylate (5) (0.700 g, 1.84 mmol) as a white solid. LCMS (ES-): m/z 371.35 [M-H]- Step-3: To a stirred solution of tert-butyl 9-(4-nitrophenyl)-3-azaspiro[5.5]undec-9-ene-3- carboxylate (5) (0.400 g, 1.07 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) was added 10% palladium on carbon wet (228.58 mg, 2.15 mmol) and the reaction mixture was stirred at 25 °C under hydrogen atmosphere in parr shaker (40 psi) for 16 hours. After completion of starting material, the reaction mixture was filtered through celite bed and washed with ethyl acetate (100 mL), concentrated under reduced pressure to afford crude which was purified by using Devisil silica in 50% ethyl acetate in petroleum ether to afford tert-butyl 9-(4- aminophenyl)-3-azaspiro[5.5]undecane-3-carboxylate (6) (0.200 g, 0.392 mmol) as grey solid. LCMS: m/z 245.24 [M-Boc+H]⁺ Step-4: To a stirred solution of tert-butyl 9-(4-aminophenyl)-3-azaspiro[5.5]undecane-3- carboxylate (6) (0. l ) i di h lf id ( mL) was added NaHCO₃ (0.487 g, 5.81 mmol, 0.225 mL) and 3-bromopiperidine-2,6-dione (7) (2.23 g, 11.61 mmol) at 25 °C. The reaction mixture was heated and stirred at 65 °C for 16 hours. The reaction mixture was quenched with water and extracted using ethyl acetate, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford crude. The crude was isolated with reverse phase (40% acetonitrile in water) to afford tert-butyl 9-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-3-azaspiro[5.5]undecane-3-carboxylate (8) (0.251 g, 0.545 mmol) as white solid. LCMS (ES⁺): m/z 456.46 [M+H]⁺ Step-5: To the stirred solution of tert-butyl 9-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-3- azaspiro[5.5]undecane-3-carboxylate (8) (0.080 g, 0.175 mmol) in dichloromethane (1 mL) was added HCl (4.0 M in 1,4-dioxane, 0.043 mL) at 0 °C and the resulting reaction mixture was allowed to stirred for 1 hour at 25 °C. The reaction mixture was concentrated under reduced pressure to afford crude compound. The crude product was triturated with diethyl ether (10 mL) to afford 3-[4-(3-azaspiro[5.5]undecan-9-yl)anilino]piperidine-2,6-dione (B-79) (0.075 mg, 0.173 mmol, 98.66% yield, 90.53% purity, hydrochloric acid) as an off-white solid. LCMS (ES⁺): m/z 356.40 [M+H]⁺ Synthesis B45: Synthesis of 3-[4-(2,7-diazaspiro [3.5] nonan-2-yl)anilino]piperidine-2,6- dione (B-80) Step-1: To a stirring solution of 1-fluoro-4-nitro-benzene (1) (8.05 g, 57.08 mmol, 6.06 mL) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (2) (10 g, 38.06 mmol, hydrochloric acid) in dimethyl sulfoxide (50 mL) was added DIPEA (24.59 g, 190.28 mmol, 33.14 mL) under nitrogen atmosphere at room temperature. The resulting reaction mixture was heated at 100 °C and stirred for 16 hours. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and quenched with ice cooled water (120 mL). The formed solid precipitate was filtered off and dried under vacuum to afford the crude. The crude was washed with petroleum ether (100 mL) to afford tert-butyl 2-(4-nitrophenyl)-2,7-diazaspiro[3.5]nonane- 7-carboxylate (3) (12 g, 33.88 mmol, 89.02% yield, 98.08% purity) as a yellow solid. LCMS (ES⁺): m/z 348 [M+H]⁺ 292.10 [M-Boc]⁺ Step-2: To a stirred solution of tert-butyl 2-(4-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7- carboxylate (3) (4 g, 11.51 mmol) in water (24.66 mL) and ethanol (73.97 mL) was added iron powder (2.57 g, 46.06 mmol, 0.32 mL) and ammonium chloride (3.70 g, 69.08 mmol, 2.42 mL) at room temperature. The reaction mixture was stirred at 85 °C for 16 hours. After completion of starting material, the reaction mixture was filtered through celite bed and washed with ethyl acetate (200 mL), concentrated under reduced pressure to afford crude. The crude was purified by column chromatography using devisal silica eluted at 50% ethyl acetate in petroleum ether to afford tert-butyl 2-(4-aminophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (4) (2.5 g, 7.64 mmol, 66.35% yield, 97% purity) as white solid. LCMS (ES⁺): m/z 318.27 [M+H]⁺ Step-3: To a stirred solution of tert-butyl 2-(4-aminophenyl)-2,7-diazaspiro [3.5] nonane-7- carboxylate (4) (1 g, 3.15 mmol) in N,N-dimethylformamide (4 mL) was added sodium bicarbonate (793.95 mg, 9.45 mmol) and 3-bromopiperidine-2,6-dione (5) (0.604 mg, 3.15 mmol) at 25 °C. The reaction mixture was stirred under nitrogen atmosphere at 90 °C for 16 hours. The reaction mixture was quenched with water and extracted using ethyl acetate, dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford crude, which was purified by reverse phase column to afford tert-butyl 2-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 6 (0.300 g, 626.85 μmol, 19.90% yield, 89.54% purity) as purple solid. LCMS (ES⁺): m/z 429.46 [M+H]⁺ Step-4: To the stirred solution of tert-butyl 2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-2,7- diazaspiro[3.5]nonane-7-carboxylate (6) (0.100 g, 0.233.36 mmol) in dichloromethane (2 mL) was added HCl (4.0 M in 1,4-dioxane, 1 mL) at 0 °C and the resulting reaction mixture was stirred for 1 hour at 25 °C. The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure afforded crude compound. The crude product was triturated in die h l h ( ) ff d ( di zaspiro [3.5] nonan-2- yl)anilino]piperidine-2,6-dione (B-80) (0.095 g, 0.185 mmol, 79.53% yield, 71.28% purity, hydrochloric acid) as a greenish solid. LCMS (ES⁺): m/z 329.44 [M+H]⁺ Synthesis of CRBN binders based on reference literature 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (B-81) Compound 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione was prepared using the method described on page 265 of WO2018237026 A1. 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (B-82) Compound 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was prepared using the method described on page 268 of WO2018237026 A1. 4-((3-(piperidin-4-yl)phenyl)amino)cyclohexane-1,3-dione (B-83) Compound 4-((3-(piperidin-4-yl)phenyl)amino)cyclohexane-1,3-dione was prepared using the method described on page 79-80 of WO2023283610 A1.

EXAMPLE 3: SYNTHESIS OF INTERMEDIATES Synthesis C1: Synthesis of 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-4- oxo-butanoic acid (C-1) Step-1: To a cooled to 0 °C solution of 4-tert-butoxy-4-oxo-butanoic acid (0.5 g, 2.87 mmol) in N,N-dimethylformamide (20 mL) was added diisopropylethylamine (2.23 g, 17.22 mmol, 3.00 mL). After 5 minutes, 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (B-81, 1.5 g, 3.74 mmol, TFA salt) was added. After 10 minutes, PyBOP (1.79 g, 3.44 mmol) was added at 0 ^oC and the reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed by brine solution and dried over with Na2SO4, filtered, and concentrated to afford tert-butyl 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-4-oxo-butanoate (0.8 g, 1.47 mmol, 51.09% yield, 81.31% purity). LCMS (ESI): m/z 444.58 [M+H]⁺. Step-2: To a cooled solution of tert-butyl 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]-4-oxo-butanoate (0.8 g, 1.80 mmol) and dichloromethane (20 mL) was added trifluoro acetic acid (1.03 g, 9.02 mmol, 694.80 μL). The reaction mixture stirred at 0 °C for 3 hours. The reaction mixture monitored by LCMS, after completion of the reaction, the reaction mixture solvent was removed under vacuum, then the crude was azeotroped with acetonitrile and toluene to afford 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-4-oxo-butanoic acid (1.0 g, 1.43 mmol, 79.27% yield, 88% purity, 062) . LCMS (ESI): m/z 388.34 [M+H]⁺. The following intermediates were prepared using identical or similar method as described above, with the corresponding CRBN binder and monoprotected diacid as starting materials. Alternative amide coupling (Step-1) conditions used include 1) HATU, DIPEA, DMF or 2) HOBt, EDC, DIPEA, DMF). Other deprotection (Step-2) condition used was 4 M HCl in dioxane, dichloromethane. Intermediate Structure Intermediate MS LCMS (ES⁺): m/z 431.23 [M+H]⁺ C-2 LCMS (ES⁺): m/z 472.53 [M+H]⁺ C-3 LCMS (ES⁺): m/z 500.48 [M+H]⁺ C-4 LCMS (ES⁺): m/z 443.1 [M+H]⁺ C-5 LCMS (ES⁺): m/z 471.2 [M+H]⁺ C-6 O LCMS (ES⁺): m/z NH 527.2 [M+H]⁺ O N O N O N OH O C-7 LCMS (ES⁺): m/z 555.2 [M+H]⁺ C-8 UPLC-MS (ES⁺): m/z 443.3 [M+H]⁺ C-9 UPLC -MS (ES⁺): m/z 471.2 [M+H]⁺ C-10 LCMS (ES⁺): m/z 527.3 [M+H]⁺ C- 11 LCMS (ES⁺): m/z 555.5 [M+H]⁺ C-12 LCMS (ES⁺): m/z 424.2 [M+H]⁺ C-13 LCMS (ES⁺): m/z 452.2 [M+H]⁺ C-14 LCMS (ES⁺): m/z 494.3 [M+H]⁺ C-15 LCMS (ES⁺): m/z 521.9 [M+H]⁺ C-16

Synthesis C2: Synthesis of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]acetic acid (C-17) Step-1: Into a 500 mL round bottom flask containing a well-stirred solution of 3-[4-(4- piperidyl)anilino]piperidine-2,6-dione (B-81, 24.5 g, 85.26 mmol, HCl salt) in anhydrous N,N- dimethylformamide (149.91 mL) was added triethylamine (43.14 g, 426.30 mmol, 59.42 mL) at 0 ^oC under nitrogen atmosphere. After 10 minutes, tert-butyl 2-bromoacetate (16.63 g, 85.26 mmol, 12.50 mL) was added and the resulting reaction mixture was stirred at 30 °C for 16 hours. After completion of the reaction as indicated by TLC, the reaction mixture was added into ice- cold water (1500 ml) to form a solid. The solid was filtered, dried under vacuum to obtain tert- butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (20.5 g, 50.55 mmol, 59.29% yield, 99% purity, no salt). LCMS (ESI): m/z 402.2 [M+H]⁺ Step-2: Into a 100 mL three-necked round-bottomed flask containing a well-stirred solution of tert-butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (21 g, 51.78 mmol, no salt) in anhydrous dichloromethane (100 mL) was added hydrogen chloride (4M in 1,4- dioxane, 99, 129.45 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford a solid. The solid was dissolved in water: acetonitrile (3:1) (200 mL) and lyophilized to afford 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetic acid (21.89 g, 51.78 mmol, 100.00% yield, 98.95% purity, hydrochloric acid*2) as an off-white solid. LCMS (ESI): m/z 346.2 [M+H]⁺ The following intermediates were prepared using identical or similar method as described above, with the corresponding CRBN binder as starting materials. Alternative S_N2 reaction (Step-1) condition used was DIPEA, DMF. Other deprotection (Step-2) condition used was TFA, dichloromethane. Intermediate Structure Intermediate MS LCMS (ES⁺): m/z 347.1 [M+H]⁺ C-18 LCMS (ES⁺): m/z 346.40 [M+H]⁺ C-19 LCMS (ES⁺): m/z 347.38 [M+H]⁺ C-20 LCMS (ES⁺): m/z 401.39 [M+H]⁺ C-21 UPLC -MS (ES⁺): m/z 401.3 [M+H]⁺ C-22 O LCMS (ES⁺): m/z 385.41 [M+H]⁺ HN O N O N N HO C-23 LCMS (ES⁺): m/z 385.2 [M+H]⁺ C-24 LCMS (ES⁺): m/z 386.3 [M+H]⁺ C-25 HO LCMS (ES⁺): m/ ⁺ N z 373.20 [M+H] O O N N O HN O C-26 LCMS (ES⁺): m/z 331.2 [M+H]⁺ C-27 OH LCMS (ES-): m/z 33 - N 0.1 [M-H] O N O N O H C-28 LCMS (ES⁺): m/z 422.40 [M+H]⁺ C-29 LCMS (ES⁺): m/z 422.3 [M+H]⁺ C-30 LCMS (ES⁺): m/z 388.26 [M+H]⁺ C-31 Synthesis C3: Synthesis of 2-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-4-piperidyl]acetic acid (C-32) Step-1: Into a 20 mL screw capped vial, a well-stirred solution of 5-bromo-1-(2,6-dibenzyloxy- 3-pyridyl)-3-methyl-benzimidazol-2-one (0.5 g, 968.27 μmol) and tert-butyl 2-(4- piperidyl)acetate (578.90 mg, 2.90 mmol) in anhydrous dioxane (8 mL) was added Cs2CO3 (946.44 mg, 2.90 mmol) at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 10 minutes. Subsequently, XPhos (92.32 mg, 193.65 μmol) was added to the reaction mixture and was degassed by bubbling nitrogen gas for 2-3 minutes and later was added Pd2(dba)3 (88.67 mg, 96.83 μmol) and degassed for another 2-3 minutes and reaction mixture was heated to 90 °C. The reaction mixtu mpletion of reaction, the reaction mixture was concentrated under reduced pressure to afford a crude solid. The crude was purified using C18 reverse phase 50 gm column in 0.1% ammonium bicarbonate in water/ acetonitrile the desired compound was collected in 70-90% and was eluted in acetonitrile. The desired compound was lyophilized to afford a product tert-butyl 2-[1-[1-(2,6-dibenzyloxy-3- pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]acetate (0.23 g, 260.89 μmol, 26.94% yield, 72% purity, no salt) as brown solid. LCMS (ESI) m/z: 635.2 [M+H]⁺. Step-2: Into a 25 mL single-neck round-bottom flask containing a well-stirred suspension of tert- butyl 2-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4- piperidyl]acetate (0.22 g, 346.59 μmol) in dioxane (6 mL) was added Pd(OH)₂ (20% on carbon (wetted with ca. 55% water)) (243.36 mg, 1.73 mmol) at ambient temperature under nitrogen atmosphere. The resulting suspension was stirred at ambient temperature under hydrogen atmosphere (bladder) for 16 hours. After complete consumption of the starting material as indicated by TLC and UPLC. The reaction mixture was filtered through a pad of Celite and Celite bed was washed with 1,4-dioxane (50 mL) and 1:1 ethyl acetate/ tetrahydrofuran (100 mL). Combined filtrate was concentrated under reduced pressure to afford a crude solid. The crude was purified using C18 reverse phase 30g column using 0.1% ammonium bicarbonate in H2O/acetonitrile. The desired compound was collected in 40-60 % and was lyophilized to afford desired compound as tert-butyl 2-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-4-piperidyl]acetate (0.07 g, 146.43 μmol, 42.25% yield, 95.5% purity, no salt). LCMS (ESI) m/z:457.2 [M+H]⁺. Step-3: Into a 50 mL round-bottom flask containing well-stirred solution of tert-butyl 2-[1-[1- (2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]acetate (0.1 g, 219.04 μmol) in anhydrous dichloromethane (3 mL) was added TFA (199.81 mg, 1.75 mmol, 134.10 μL) dropwise at 0 ^oC under nitrogen atmosphere and the reaction was allowed to stir for 3 hours at 0 ^oC to room temperature. After completion of reaction, the reaction mixture was concentrated under reduced pressure and was triturated 2-3 times with dichloromethane and toluene to afford 2-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]acetic acid (C- 32) (0.095 g, 181.32 μmol, 82.78% yield, 98.19% purity, trifluoroacetic acid) as crude yellow fluid. LCMS (ESI): m/z 401.0 [M+H]⁺. The following intermediates were prepared using identical or similar method as described above, with the corresponding bis benzyloxy pyridine as starting material. Alternative deprotection (Step-3) condition used was 4M HCl in dioxane, dichloromethane. Bis benzyloxy pyridine Intermediate Structure Intermediate MS HO LCMS (ESI): m/z 385.43 O ^N _N [M+H]⁺ N O HN O C-33 Synthesis C4: Synthesis of 2-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-4-piperidyl]acetic acid (C-34) Step-1: To a stirred solution of 4-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol- 2-one (2 g, 3.87 mmol, no salt) and ethyl 2-(4-piperidyl)acetate (1.99 g, 11.62 mmol, no salt) in toluene (30 mL) was added sodium tert-butoxide (1.12 g, 11.62 mmol, 1.09 mL) at 25 °C under nitrogen purging, RuPhos (361.46 mg, 774.62 μmol) and (1E,4E)-1,5-diphenylpenta-1,4-dien- 3-one;palladium (354.66 mg, 387.31 μmol) was added. Then the reaction mixture was heated to 90 °C for 16 hours. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate, washed with water and brine solution. The collected organic layer was dried over with sodium sulphate, filtered, and concentrated under reduced pressure to afford crude compound. whi h ifi d b fl h l h t h using 230-400 silica gel, eluted with 30-40% ethyl acetate in petroleum ether to ethyl 2-[1-[1-(2,6-dibenzyloxy-3- pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]acetate (1.6 g, 572.27 μmol, 14.78% yield, 21.7% purity, no salt) as a solid. LCMS (ES+): m/z 607.36 [M+H]⁺ Step-2: To a stirred solution of ethyl 2-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-4-yl]-4-piperidyl]acetate (1.5 g, 2.47 mmol, no salt) in tetrahydrofuran (10 mL) was added lithium hydroxide monohydrate, 98% (414.99 mg, 9.89 mmol) at 0 °C and the reaction mixture was allowed to stirred at 25 °C for 16 hours . After complete consumption of the starting material, the reaction mixture was acidified with citric acid and was extracted with ethyl acetate. The collected organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure, to 2-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-4-yl]-4-piperidyl]acetic acid (0.5 g, 765.39 μmol, 30.96% yield, 88.58% purity, no salt) as a solid. LCMS (ES⁺): m/z 579.73 [M+H]⁺ Step-3: To a stirred solution of 2-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-4-yl]-4-piperidyl]acetic acid (0.2 g, 345.63 μmol, no salt) in ethyl acetate (10 mL) and tetrahydrofuran (10 mL) was added palladium, 10% on carbon, Type 487, dry (183.91 mg, 1.73 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred in hydrogen atmosphere under balloon pressure for 16 hours. Subsequently, it was filtered through celite bed and washed with ethyl acetate (25 mL). The filtrate was concentrated under reduced pressure to afford 2-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4- piperidyl]acetic acid (C-34) (0.07 g, 169.60 μmol, 49.07% yield, 97.02% purity, no salt) as colorless gel, which was used for next step without further purification. LCMS (ES⁺): m/z 401.41 [M+H]⁺ Synthesis C5: Synthesis of 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)cyclohexyl)acetic acid (C-35)

Step-1: To a stirred solution of ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)cyclohex-3-en-1-yl]acetate (2) (478.56 mg, 1.63 mmol) and 5-bromo-1-(2,6-dibenzyloxy-3- pyridyl)-3-methyl-benzimidazol-2-one (1) (0.700 g, 1.36 mmol) in 1,4-dioxane (10 mL) and water (2 mL), was added sodium carbonate (431.03 mg, 4.07 mmol, 170.23 μL) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes before adding Pd(dppf)Cl2 (99.19 mg, 135.56 μmol) and the reaction was stirred at 100 °C for 16 hours. Subsequently, the reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by column chromatography using Davisil silica in 20% ethyl acetate in petroleum ether as eluent to ethyl 2-(4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)cyclohex-3-en-1-yl)acetate (3) (0.550 g, 754.07 μmol, 55.63% yield, 82.77% purity ) as light brown gum. LCMS (ES⁺): m/z 604.41[M+H] ⁺ Step-2: To a stirred solution of ethyl 2-(4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)cyclohex-3-en-1-yl)acetate (3) (500 mg, 824.12 μmol, no salt) in water (5 mL) and tetrahydrofuran (20 mL), was added LiOH (78.94 mg, 3.30 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 3 hours. After completion the reaction mixture was concentrated under reduced pressure to afford crude residue which was diluted with water (20 mL) and acidified with 4 N HCl and extracted with ethyl acetate (50 mL), the ethyl acetate layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford 2-[4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo- benzimidazol-5-yl]cyclohex-3-en-1-yl]acetic acid (4) (0.4 g, 459.03 μmol, 55.70% yield, 66.06% purity,) as a gummy. LCMS: m/z 576.44 [M+H] ⁺ Step-3: A stirred solution of 2-(4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)cyclohex-3-en-1-yl)acetic acid (4) (0.05 g, 86.86 μmol ) in ethyl acetate (20 mL) and tetrahydrofuran (20 mL) was degassed with nitrogen for 10 minutes and then Pd/C (100 mg, 939.67 μmol) was added at room temperature. The reaction mixture was stirred under hydrogen atmosphere using balloon pressure for 16 hours. After completion of the reaction, the mixture was filtered through celite bed and washed with ethyl acetate (100 mL).The filtrate was concentrated under reduced pressure to afford the crude product, which was triturated with diethyl ether (20 mL) to afford 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)cyclohexyl)acetic acid C-35 (0.008 g, 17.71 μmol, 20.40% yield, 88.45% purity) as an off-white solid. LCMS (ESI): m/z 400.42 [M+H]⁺. The following intermediate was prepared substantially following the method described above, using the corresponding bis benzyloxy pyridine as starting material. Bis benzyloxy pyridine Intermediate Structure Intermediate MS LCMS (ES+): m/z 384.34 [M+H]⁺ C-36 Synthesis C6: Synthesis of 3-[3-methyl-2-oxo-5-[1-(4-piperidyl)-4-piperidyl]benzimidazol- 1-yl]piperidine-2,6-dione (C-37) O O O O HN HN O HN N O 4 M HCl i O O N n dioxane N Boc N DCM N O AcOH, NaOAc N Step-2 O MP-BH₃CN N DMSO N N Step-1 N N Boc HN H Step-1: Into a 25 mL round-bottom flask containing a well stirred solution of 3-[3-methyl-2-oxo- 5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (200 mg, 516.95 μmol) and tert-butyl 4- oxopiperidine-1-carboxylate (154.50 mg, 775.43 μmol) in dimethyl sulfoxide (534.45 μL) was added acetic acid (310.44 mg, 5.17 mmol, 295.94 μL) and sodium acetate (169.63 mg, 2.07 mmol, 169.63 μL) at ambient temperature. The resulting reaction mixture was allowed to stirred for 3 hours at room temperature under nitrogen atmosphere, then mp cyanoborohydride (100 mg) was added into the reaction mixture and the reaction was allowed to stir overnight. Progress of reaction was monitored by UPLC. After completion of the reaction, the reaction mixture was concentrated under vacuum. The crude residue was dissolved with water, the aqueous layer was extracted twice with ethyl acetate and washed with brine followed by saturated bicarbonate solution, and dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum to afford crude tert-butyl 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]piperidine-1-carboxylate (200 mg, 304.39 μmol, 58.88% yield, 80% purity, no salt) as a brown solid. LCMS (ESI): m/z 526.2 [M+H]⁺. Step-2: Into a 100 mL round-bottom flask containing a well-stirred solution of tert-butyl 4-[4- [1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]piperidine-1- carboxylate (200 mg, 304.39 μmol) in anhydrous dichloromethane (3.31 mL) was added HCl (4.0 M in 1,4-dioxane, 760.98 μL) at 0 °C under N2 atmosphere. The resulting mixture was stirred for an hour at room temperature. Progress of the reaction was monitored by UPLC-MS. After completion of the reaction, solvent was evaporated under reduced pressure to afford 3-[3- methyl-2-oxo-5-[1-(4-piperidyl)-4-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-37) (120 mg, 215.59 μmol, 70.83% yield, 83% purity, hydrochloric acid) as a brown fluffy solid. LCMS (ESI): m/z 426.2 [M+H]⁺. The following intermediate was prepared using identical or similar method as described above, with the corresponding CRBN binder and ketone as starting materials. Alternative reductive amination (Step-1) condition was TEA, STAB, THF. Other deprotection (Step-2) condition was TFA, dichloromethane. CRBN binder Ketone Intermediate Structure Intermediate MS LCMS (ESI): m/z 371.42 [M+H]⁺ C-38 The following intermediates are prepared using identical or similar method as described above, with the corresponding CRBN binder and ketone as starting materials. Alternative reductive amination (Step-1) condition is TEA, STAB, THF. Other deprotection (Step-2) condition is TFA, dichloromethane. CRBN binder Ketone Intermediate Structure C- 39 C-40 C-41

C-42 C-44 C-45 466 Synthesis C7: Synthesis of 3-[3-methyl-2-oxo-5-[1-(4-piperidylmethyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-46) Step-1: To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (0.2 g, 584.13 μmol) and tert-butyl 4-formylpiperidine-1-carboxylate (124.58 mg, 584.13 μmol) in 1,2-dichloroethane (2 mL) and methanol (2 mL) at room temperature was added sodium acetate (191.67 mg, 2.34 mmol, 125.44 μL) and acetic acid (35.08 mg, 584.13 μmol) at 0 °C. The reaction mixture was stirred at room temperature for 13 hours. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with water and extracted with dichloromethane and washed with brine. The organic layer was dried over sodium sulfate, filtered and then evaporated under reduced pressure to afford crude product which was purified by combi-flash column chromatography to afford tert-butyl 4-[[4-[1-(2,6- dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]methyl]piperidine-1- carboxylate (0.107 g, 174.28 μmol, 29.84% yield, 87.90% purity). LCMS (ESI): m/z 540.43 [M+H]⁺. Step-2: To the stirred solution of tert-butyl 4-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]methyl]piperidine-1-carboxylate (50 mg, 92.65 μmol, no salt) in dichloromethane (1 mL) was added HCl (4.0 M in 1,4-dioxane, 0.5 mL) at 0 °C and the resulting reaction mixture was stirred for 3 hours at 25 °C . The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain crude compound. The crude product was triturated in diethyl ether (5 mL). Diethyl ether layer was decanted and dried under reduced pressure to afford 3-[3-methyl-2-oxo-5-[1-(4-piperidylmethyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-46) (40 mg, 80.67 μmol, 87.07% yield, 96% purity, hydrochloric acid) as off-white solid. LCMS (ESI): m/z 440.62 [M+H]⁺. The following intermediates were prepared using identical or similar method as described above, with the corresponding CRBN binder and aldehyde as starting materials. Alternative reductive amination (Step-1) conditions were 1) TEA, AcOH, NaBH₃CN, DMAc or 2) TEA, STAB, THF. Other deprotection (Step-2) condition was TFA, dichloromethane. LCMS (ESI): m/z 461.2 [M+H]⁺ C-54 LCMS (ESI): m/z 425.69 [M+H]⁺ C-56 LCMS (ESI): m/z 411.27 [M+H]⁺ C-57 LCMS (ESI): m/z 411.45 [M+H]⁺ C-58 The following intermediates are prepared using identical or similar method as described above, with the corresponding CRBN binder and aldehyde as starting materials. Alternative reductive amination (Step-1) conditions are 1) TEA, AcOH, NaBH3CN, DMAc or 2) TEA, STAB, THF. Othe hloromethane. CRBN binder Aldehyde Intermediate Structure C-55 C-59 C-60 C-61

CRBN binder Aldehyde Intermediate Structure C-62 C-63 C-64 C-65 CRBN binder Aldehyde Intermediate Structure O HN O N N HN N N O C-66 C-67 C-68 C-69 Chiral purification using SFC is needed. CRBN binder Aldehyde Intermediate Structure C-70 Chiral purification using SFC is needed. Synthesis C8: Synthesis of 3-[1-methyl-6-[4-(4-piperidylmethyl)-1-piperidyl]indazol-3- yl]piperidine-2,6-dione (C-71): O HN O H₂, Pd/C, EtOAc/THF N N 4M HCl in 1,4-dioxane, RT, 16 h BocN N 1,4-dioxane,RT,2 h Step-2 ⁴ _Step-3

Step-1: To a stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 1 (0.5 g, 0.999 mmol) and tert-butyl 4-(4-piperidylmethyl)piperidine-1-carboxylate 2 (338.64 mg, 1.20 mmol) in toluene (10 mL) was added sodium tert-butoxide (288.08 mg, 3.00 mmol) and degassed with nitrogen gas for 5 minutes. BINAP (186.66 mg, 0.299 mmol) and tris(dibenzylideneacetone)dipalladium(0) (91.50 mg, 0.099 mmol) were then added. The reaction mixture was heated to stir at 90 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to get crude which was purified by column chromatography using (100- 200 silica gel) eluted at 30-40% ethyl acetate in petroleum ether to afford tert-butyl 4-[[1-[3- (2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-4-piperidyl]methyl]piperidine-1- carboxylate 3 (0.3 g, 39% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 702.84 [M+H]⁺. Step-2: To a solution of tert-butyl 4-[[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]- 4-piperidyl]methyl]piperidine-1-carboxylate 3 (0.3 g, 0.427 mmol) in ethyl acetate (3 mL) and tetrahydrofuran (3 mL) was added 10% Pd/C (0.3 g, 2.82 mmol) at room temperature. The resulting mixture was shaken under hydrogen atmosphere (60 psi) using parr shaker for 16 hours. The reaction mixture was filtered, washed and the filtrate was concentrated under reduced pressure to get the crude which was triturated with diethyl ether (10 mL) to afford tert-butyl 4- [[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-4-piperidyl]methyl]piperidine-1- carboxylate 4 (0.09 g, 30% yield) as an off-white solid. LC-MS (ES⁺): m/z 524.72[M+H]⁺. Step-3: A stirred solution of tert-butyl 4-[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]- 4-piperidyl]methyl]piperidine-1-carboxylate 4 (0.03 g, 0.057 mmol) in 1,4-dioxane (5 mL) was cooled to 0 °C and 4M HCl solution in 1, 4-dioxane (1 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to get the crude which was triturated with diethyl ether (5 mL) to afford 3-[1-methyl-6-[4-(4-piperidylmethyl)-1-piperidyl]indazol-3-yl]piperidine-2,6-dione C-71 (0.02 g, 67% yield, HCl salt) as a blue solid.LC-MS (ES⁺): m/z 424.37 [M+H]⁺.¹ H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1H), 8.10-7.50 (m, 1H), 7.40-6.60 (m, 2H), 4.35 (s, 1H), 3.96 (s, 3H), 3.75-3.65 (m, 2H), 3.65-3.55 (m, 1H), 3.30-2.90 (m, 4H), 2.90-2.75 (m, 2H), 2.75-2.55 (m, 2H), 2.40-2.30 (m, 1H), 2.20-2.10 (m, 1H), 2.00-1.45 (m, 8H), 1.40-1.10 (m, 4H). Synthesis C9: Synthesis of 3-[4-[1-[2-(4-piperidyl)ethyl]-4-piperidyl]anilino]piperidine- 2,6-dione (C-75) Step-1: To a stirred solution of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (B-81, 0.5 g, 1.25 mmol, trifluoroacetic acid) in tetrahydrofuran (3 mL) was added TEA (378.15 mg, 3.74 mmol, 520.87 μL) at 25 °C then added tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (283.15 mg, 1.25 mmol, no salt) portion wise at 25 °C. The reaction mixture was stirred under nitrogen atmosphere at 25 °C for 16 hours, then added STAB (264.02 mg, 1.25 mmol) at 0 °C. The progress of reaction was monitored by TLC/LCMS. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate (200 ml) and filtered through celite bed. Then added water and extracted product using ethyl acetate, dried over sodium sulphate, filtered, and concentrated under reduced pressure, which was column purified using (Davisil silica) with 10% methanol in dichloromethane as an eluent to afford tert-butyl 4-[2-[4-[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]ethyl]piperidine-1-carboxylate (0.38 g, 679.67 μmol, 54.56% yield, 89.19% purity) as a pale green solid. LCMS (ESI): m/z 499.40 [M+H]⁺ Step-2: To the stirred solution of tert-butyl 4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]ethyl]piperidine 1 carboxylate (100 mg 20054 μmol no salt) in dichloromethane (1 mL) was added hydrogen chloride (4.0 M in 1,4-dioxane, 1 mL) at 0 °C, and the reaction was stirred for 2 hours at 25 C .The reaction progress was monitored by TLC and LCMS. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure to afford crude product. The crude product was triturated with diethyl ether (30 ml) to afford 3-[4-[1-[2-(4-piperidyl)ethyl]-4-piperidyl]anilino]piperidine-2,6-dione (C-75) (100 mg, 197.70 μmol, 98.58% yield, 86% purity, hydrochloric acid) as an off-white solid. LCMS (ESI): m/z 399.36 [M+H]⁺ The following intermediate was prepared using identical or similar method as described above, with the corresponding CRBN binder and aldehyde as starting materials. Alternative reductive amination (Step-1) conditions were 1) NaOAc, AcOH, Si-CBH, methanol, DCE; 2) NaBH3CN, AcOH CRBN binder Aldehyde Intermediate Structure Inter media te MS LCMS (ESI): m/z 554.39 [M+H] + C-76 The following intermediates are prepared using identical or similar method as described above, with the corresponding CRBN binder and aldehyde as starting materials. Alternative reductive amination (Step-1) conditions are 1) NaOAc, AcOH, Si-CBH, methanol, DCE; 2) NaBH3CN, AcOH

CRBN binder Aldehyde Intermediate Structure C-77 C-78 C-79 C-80 CRBN binder Aldehyde Intermediate Structure C-81 C- 82 C- 83 C-84 CRBN binder Aldehyde Intermediate Structure C-85 C-86 C-87

Synthesis C10: Synthesis of afford 3-[3-methyl-2-oxo-5-[1-(2-piperazin-1-ylethyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-88) O Boc HN N H N _O O N Br O Boc N N N DIPEA, D N O MF N N Step-1 N _O HN Step-1: Into a 20 mL vial containing a well-stirred solution of tert-butyl 4-(2- bromoethyl)piperazine-1-carboxylate (300 mg, 818.55 μmol) were added DIPEA (317.37 mg, 2.46 mmol, 427.72 μL) and 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (350.33 mg, 818.55 μmol) at 70 °C, and stirred at ambient temperature for 16 hours. After completion of the reaction indicated by UPLC, the reaction mixture was diluted with water (20 mL) and the product was extracted with ethyl acetate (2 x 40 mL). Combined organic phases were washed with cold water (30 mL), dried (anhydrous Na₂SO₄), filtered, and the filtrate was concentrated under reduced pressure to afford a crude tert-butyl 4-[2-[4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethyl]piperazine-1-carboxylate (330 mg, 279.62 μmol, 34.16% yield, 47% purity, no salt) as light brown sticky solid. LC-MS (ESI): m/z 555.4 [M+H]⁺. Step-2: Into a 50 mL single-necked round-bottomed flask containing a well-stirred solution of tert-butyl 4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-3H-benzimidazol-5-yl]-1- piperidyl]ethyl]piperazine-1-carboxylate (200 mg, 173.86 μmol) in anhydrous dichloromethane (9.56 mL) was added 4.0 M HCl in 1,4-dioxane (434.66 μL) at 0 °C under nitrogen atmosphere. The contents were stirred for 16 hours at ambient temperature. After consumption of the starting material as indicated by UPLC, excess solvent was removed from the reaction mixture under reduced pressure to afford a crude mass. The crude product was washed with MTBE (10 mL) to afford 3-[3-methyl-2-oxo-5-[1-(2-piperazin-1-ylethyl)-4-piperidyl]benzimidazol-1- yl]piperidine-2,6-dione (C-88) (70 mg, 150.91 μmol, 86.80% yield, 98% purity) as a grey solid. LCMS (ESI): m/z 455.3 [M+H]⁺. The following intermediates were prepared substantially following the method described above, using the corresponding CRBN binder and bromide as starting materials. CRBN binder Bromide Intermediate Structure Intermediate MS LCMS (ESI): m/z 400.39 [M+H]⁺ C-89 LCMS (ESI): m/z 468.57 [M+H]⁺ C-90

Synthesis C11: Synthesis of 3-[3-methyl-2-oxo-5-[1-(piperazine-1-carbonyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-91) Step-1: Into a 20mL vial containing a well stirred solution of 3-[3-methyl-2-oxo-5-(4- piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (250 mg, 730.16 μmol) in dichloromethane (4.24 mL) and DMA (1mL) were added TEA (369.42 mg, 3.65 mmol, 508.85 μL) and 4- nitrophenyl) carbonochloridate (17.66 mg, 87.62 μmol) at 0 °C.The reaction mixture was stirred at room temperature for 16 hours. Thereafter, the mixture was diluted with water (150 mL) and extracted with dichloromethane (2 x 70 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product which was co-distilled with toluene (7 mL) and washed with MTBE (10mL) to afford (4-nitrophenyl) 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (200 mg, 326.27 μmol, 44.68% yield, 82.79% purity, no salt) as a pale yellow solid. LC-MS (ESI):m/z 508.2 [M+H]⁺. Step-2: Into a 20mL vial containing a well stirred solution of (4-nitrophenyl) 4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (200 mg, 346.80 μmol) in N,N-dimethylformamide (4 mL) was added DIPEA (224.10 mg, 1.73 mmol, 302.03 μL) and tert-butyl piperazine-1-carboxylate (71.05 mg, 381.48 μmol) The reaction mixture was stirred at 90 °C for 4 hours. The reaction was monitored by UPLC/TLC. The solvent was removed from the reaction mixture to afford crude product which was purified by reverse phase [Redisef-RF C18 column 120g, mobile phase: 0.1% HCOOH in water : acetonitrile] to afford tert-butyl 4-[4- [1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1- carbonyl]piperazine-1-carboxylate (140 mg, 252.42 μmol, 72.78% yield, no salt) a pale yellow solid. LCMS (ESI): m/z 455.2 [M-Boc+H]^{+ .} Step-3: Into a 50 mL single-necked round-bottomed flask containing a well stirred solution of tert-butyl 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1- carbonyl]piperazine-1-carboxylate (120 mg, 214.19 μmol) in dioxane (3.46 mL) was added HCl (4.0 M in 1,4-dioxane, 535.49 μL) at 0 °C and the resulting solution was stirred at room temperature for two hours and the progress was monitored by LCMS. Thereafter, the reaction mixture was concentrated under reduced pressure get the residue and triturated with MTBE (5mL) to afford 3-[3-methyl-2-oxo-5-[1-(piperazine-1-carbonyl)-4-piperidyl]benzimidazol-1- yl]piperidine-2,6-dione (C-91) (100 mg, 203.51 μmol, 95.01% yield, 99.92% purity, hydrochloric acid) as a pale yellow solid. LCMS (ESI): m/z 455.2 [M+H]⁺. Synthesis C12: Synthesis of 3-[4-[1-(piperazine-1-carbonyl)-4- piperidyl]anilino]piperidine-2,6-dione (C-92) Step-1: To a stirred solution of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (B-81, 250 mg, 870.00 μmol) in dichloromethane was added triphosgene (258.17 mg, 870.00 μmol) and DIPEA (449.76 mg, 3.48 mmol, 606.15 μL) and the reaction mixture was stirred for 1 hour at 0 °C.1- Boc-piperazine (162.04 mg, 870.00 μmol) was added and the reaction mixture was stirred for 16 hours at room temperature. The progress of the reaction was monitored by LCMS. On completion, the sol d i d h id was purified by column chromatography using 5% methanol in dichloromethane as eluent to provide tert-butyl 4-[4-[4- [(2,6-dioxo-3-piperidyl)amino]phenyl]piperidine-1-carbonyl]piperazine-1-carboxylate (180 mg, 347.43 μmol, 39.93% yield, 96.43% purity) as off-white solid. LCMS (ESI): m/z 498.39 [M-H]-. Step-2: To a stirred solution of tert-butyl 4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]piperidine-1-carbonyl]piperazine-1-carboxylate (100 mg, 200.16 μmol) in dichloromethane (2 mL) was added 4.0 M HCl in 1,4-dioxane (0.5 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for an hour. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure to afford crude product, which was triturated with diethyl ether (3 mL x 2) to afford 3-[4-[1-(piperazine-1-carbonyl)-4- piperidyl]anilino]piperidine-2,6-dione (C-92) (90 mg, 176.16 μmol, 88.01% yield, 85.33% purity, hydrochloric acid) as an off-white solid. LCMS (ESI): m/z 400.49 [M+H]⁺. Synthesis C13: Synthesis of 3-[3-methyl-2-oxo-5-[1-(2-piperazin-1-ylacetyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-93) Step-1: To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (0.250 g, 547.75 μmol, trifluoroacetic acid) and 2-(4-tert-butoxycarbonylpiperazin-1- yl)acetic acid (93.67 mg, 383.42 μmol) in N,N-dimethylformamide (5 mL) was added DIPEA (176.98 mg, 1.37 mmol, 238.52 μL) at 0 °C and the solution was stirred from 0 °C to room temperature for 10 minutes. then HATU (312.40 mg, 821.62 μmol) was added and continue the stirring at room temperature for 2 hours. The progress of the reaction was monitored by LCMS and TLC. After completion the reaction mixture was directly evaporated under reduced pressure to afford crude product which was purified by Prep- HPLC purification to afford tert-butyl 4-[2- [4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-2-oxo- ethyl]piperazine-1-carboxylate (0.18 g, 305.93 μmol, 55.85% yield, 96.65% purity) as a white solid. LCMS (ES+): m/z 569.47 [M+H]⁺. Step-2: To the stirred solution of tert-butyl 4-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-2-oxo-ethyl]piperazine-1-carboxylate (100 mg, 175.85 μmol, no salt) in dichloromethane (1 mL) was added 4.0 M HCl in 1,4-dioxane (1 mL) at 0 °C and the resulting reaction mixture was stirred for 1 hour at 25 °C . The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain crude compound. The crude product was triturated in diethyl ether (5 mL). Diethyl ether layer was decanted and dried under reduced pressure to afford 3-[3-methyl-2-oxo-5-[1-(2-piperazin-1- ylacetyl)-4-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-93) (90 mg, 168.23 μmol, 95.67% yield, 94.40% purity, hydrochloric acid) as off white solid. LCMS (ES+): m/z 469.32 [M+H]⁺. The following intermediates were prepared using identical or similar method as described above, with the corresponding CRBN binder and carboxylic acid as starting material. Alternative amide coupling (Step-1) conditions included 1) triphosgene, DIPEA, MeCN, DCM. Other deprotection (Step-2) condition used was TFA, DCM. CRBN binder Carboxylic Intermediate Structure Intermediate acid MS LCMS (ES+): m/z 468.49 [M+H]⁺ C-94 Synthesis C14: Synthesis of 3-[3-methyl-5-[1-[2-(methylamino)ethyl]-4-piperidyl]-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (C-99) Step-1: Into a 20 ml glass containing a solution of tert-butyl N-methyl-N-(2-oxoethyl)carbamate (116.86 mg, 674.67 μmol) and 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (200mg, 449.78 μmol) in anhydrous dimethyl sulfoxide (2 mL) were added sodium acetate, anhydrous (110.69 mg, 1.35 mmol, 72.44 μL) and acetic acid (270.10 mg, 4.50 mmol, 259.71 μL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 hours at room temperature. After that, MP-Cyanoborohydride; 2mmol/g (250 mg, 899.56 μmol) was added to the resultant reaction mixture and stirring was continued for 16 hours at 70 °C temperature. After the completion of reaction as per UPLC, the reaction mixture was filtered through celite bed and filtrate was concentrated under reduced pressure to afford the crude purified column chromatography [Purification method: Column: RediSep C 18-30g, Mobile phase: A: 0.1% ammonium bicarbonate in water, B: acetonitrile, fractions were lyophilized to afford tert-butyl N-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]ethyl]-N-methyl-carbamate (80 mg, 150.52 μmol, 33.47% yield, 94% purity) as an off- white solid. LCMS (ESI): m/z 500.2 [M+H]⁺. Step-2: Into a 25 mL round-bottom flask containing a well-stirred solution of tert-butyl N-[2-[4- [1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethyl]-N-methyl- carbamate (80 mg, 150.52 μmol) in anhydrous dichloromethane (1.78 mL) was added 4 M hydrogen chloride in 1,4-dioxane, 99% (376.30 μL) at 0 °C under N2 atmosphere. The resulting mixture was stirred for 1 hour at room temperature. After completion of the reaction solvents were evaporated under reduced pressure to afford the crude 3-[3-methyl-5-[1-[2- (methylamino)ethyl]-4-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (C-99) (50 mg, 107.81 μmol, 71.63% yield, 94% purity, hydrochloric acid) as an off-white fluffy solid. LCMS (ESI): m/z 400.3 [M+H]⁺. The following intermediates were prepared using identical or similar method as described above, with the corresponding CRBN binder and aldehyde as starting material. Alternative reductive amination (Step-1) condition includes NaOAc, AcOH, Si-CBH, DCE, methanol. Intermediate Structure Intermediate MS LCMS (ESI): m/z 414.34 [M+H]⁺. C-100 LCMS (ESI): m/z 428.39 [M+H]⁺. C-101 LCMS (ESI): m/z 345.27 [M+H]⁺. C-102 LCMS (ESI): m/z 359.39 [M+H]⁺. C-103 LCMS (ESI): m/z 373.51 [M+H]⁺. C-104 Synthesis C15: Synthesis of 3-[3-methyl-5-[1-[5-(methylamino)pentyl]-4-piperidyl]-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (C-105) Step-1: To a stirred solution of tert-butyl N-(5-hydroxypentyl)-N-methyl-carbamate (0.5 g, 2.30 mmol, no salt) in dichloromethane (15 mL) was added TEA (465.66 mg, 4.60 mmol, 641.41 μL) dropwise and methanesulfonyl chloride (316.29 mg, 2.76 mmol, 214.14 μL, no salt) at 0 °C under N₂ atmosphere. The reaction mixture was stirred at room temperature for 4 hours .The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3 x 15 mL). The combined organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product 5-[tert- butoxycarbonyl(methyl)amino]pentyl methanesulfonate (0.55 g, 1.58 mmol, 68.78% yield, 85% purity, no salt) as a yellow gummy solid. Step-2: To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (0.5 g, 1.46 mmol, no salt) in acetonitrile (10 mL) was added DIPEA (943.67 mg, 7.30 mmol, 1.27 mL) at 25 °C, then 5-[tert-butoxycarbonyl(methyl)amino]pentyl methanesulfonate (560.78 mg, 1.90 mmol, no salt) was added portion wise at 25 °C. The reaction mixture was stirred under nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The collected organic layer was dried over with sodium sulphate, filtered, and then concentrated under reduced pressure to afford crude compound. which was purified by column chromatography using (Davisil silica) with 70% ethyl acetate in petroleum ether as an eluent to afford tert-butyl N-[5-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]pentyl]-N-methyl-carbamate (0.15 g, 238.15 μmol, 16.31% yield, 86% purity, no salt) as an off-white solid. LCMS (ES⁺): m/z 542.52 [M+H]⁺. Step-3: To the stirred solution of tert-butyl N-[5-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]pentyl]-N-methyl-carbamate (50 mg, 92.31 μmol, no salt) in dichloromethane (1 mL) was added 4.0 M HCl in 1,4-dioxane (500.00 μL) at 0 °C and the resulting reaction mixture was stirred for 1 hour at 25 °C . The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain crude compound. The crude product was triturated in diethyl ether (5 mL). Diethyl ether layer was decanted and dried under reduced pressure to afford 3-[3-methyl-5-[1-[5-(methylamino)pentyl]- 4-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (C-105) (50 mg, 65.76 μmol, 71.24% yield, 62.87% purity, hydrochloric acid) as an off-white solid. LCMS (ES⁺): m/z 442.48 [M+H]⁺. The following intermediate was prepared substantially following the method as described above, using the corresponding CRBN binder and alcohol as starting material. Intermediate Structure Intermediate MS LCMS (ES+): m/z 387.44 [M+H]⁺. C-106 Synthesis C16: Synthesis of 3-(7-([1,4'-bipiperidin]-4-yl)benzo[d]isoxazol-3-yl)piperidine- 2,6-dione (C-43): Step-1: To a stirred solution of 3-[7-(4-piperidyl)-1, 2-benzoxazol-3-yl] piperidine-2, 6-dione 1 (0.4 g, 1.14 mmol, HCl salt) and tert-butyl 4-oxopiperidine-1-carboxylate 2 (273.40 mg, 1.37 mmol) in tetrahydrofuran (7 mL) was added triethylamine (0.478 mL, 3.43 mmol) at room temperature. The reaction mixture was heated to stir at 70 °C for 16 hours, then cooled to 0 °C. Sodium cyanoborohydride (143.72 mg, 2.29 mmol) was added and allowed to stir at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was washed with water (20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude which was purified by reverse phase (80 g, C18 column) using 20-25% acetonitrile in water to afford tert-butyl 4-[4-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-7-yl]-1- piperidyl]piperidine-1-carboxylate 3 (0.25 g, 44% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 441.33 [M-tBu]⁺.¹H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 7.67 (d, J = 8.00 Hz, 1H), 7.49 (d, J = 6.80 Hz, 1H), 7.32 (t, J = 7.20 Hz, 1H), 4.59 (dd, J = 4.80, 12.00 Hz, 1H), 3.98 (d, J = 11.60 Hz, 2H), 3.05-2.95 (m, 3H), 2.90-2.70 (m, 3H), 2.65-2.55 (m, 2H), 2.50-2.40 (m, 1H), 2.40-2.30 (m, 2H), 2.25-2.15 (m, 1H), 1.95-1.70 (m, 6H), 1.50-1.30 (m, 11 H). Step-2: To a stirred solution of tert-butyl 4-[4-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-7-yl]-1- piperidyl]piperidine-1-carboxylate 3 (150 mg, 302.06 μmol, no salt) in dichloromethane (2 mL) was added HCl (4.0 M in 1,4-dioxane) (11.01 mg, 302.06 μmol) at 0 ℃. The resulting reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was evaporated to get the crude which after diethyl ether wash afforded 3-[7-[1-(4-piperidyl)-4-piperidyl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione C-43 (130 mg, 224.24 μmol, 74.24% yield, 74.68% purity, hydrochloric acid) as white solid. LCMS (ES⁺): m/z 397.55[M+H]⁺. Synthesis C17: Synthesis of 1-[6-(3, 9-diazaspiro [5.5]undecan-3-yl)-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione (C-72): Step-1: To a stirred solution of 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4- dione 1 (2 g, 6.19 mmol) in N,N-dimethylformamide (30 mL) was added cesium carbonate (2.75 g, 15.47 mmol) and 1-(chloromethyl)-4-methoxy-benzene (1.26 g, 8.05 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with cold water, the precipitated solid was filtered, dried to afford 1-(6-bromo-1-methyl-indazol-3- yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione 2 (2.4 g, 79% yield) as an off- white solid. LCMS (ESI): m/z 443.47 [M+H]⁺. Step-2: To a stirred solution of 1-(6-bromo-1-methyl-indazol-3-yl)-3-[(4-methoxyphenyl)- methyl]hexahydropyrimidine-2,4-dione 2 (1 g, 2.26 mmol) and tert-butyl 4-(4- piperidylmethyl)piperidine-1-carboxylate 3 (828.23 mg, 2.93 mmol) in 1,4-dioxane (15 mL) was added K₃PO₄ (1.44 g, 6.77 mmol) and degassed with nitrogen gas for 10 minutes. XPhos-Pd-G₃ (152.76 mg, 180.47 μmol) was added, and the resulting mixture was heated at 100 °C for 16 hours. The reactio i d i h rude product which was purified by flash chromatography (100-200 silica gel) using 30-40% ethyl acetate in petroleum ether as an eluent to afford tert-butyl 4-[[1-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo- hexahydropyrimidin-1-yl]-1-methyl-indazol-6-yl]-4-piperidyl]methyl]piperidine-1-carboxylate 4 (0.6 g, 35% yield) as a yellow solid. LCMS (ESI): m/z 645.91 [M+H]⁺. Step-3: To a stirred solution of tert-butyl 4-[[1-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo- hexahydropyrimidin-1-yl]-1-methyl-indazol-6-yl]-4-piperidyl]methyl]piperidine-1-carboxylate 4 (0.3 g, 465.26 μmol) in dichloromethane (4 mL) at 0 °C was added trifluoromethanesulfonic acid (1.40 g, 9.31 mmol) and trifluoroacetic acid (530.49 mg, 4.65 mmol). The reaction mixture was allowed to stir at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure to get crude residue which was triturated with diethyl ether (20 mL) to afford 1-[1-methyl-6-[4-(4-piperidylmethyl)-1-piperidyl]indazol-3-yl]hexahydropyrimidine- 2,4-dione trifluoromethanesulfonic acid C-72 (250 mg, 88% yield) as an off-white solid. LCMS (ESI): m/z 425.36 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6): δ 10.52 (s, 1H), 8.45-8.35 (m, 1H), 8.15-8.05 (m, 1H), 7.52-7.51 (m,1H), 7.01-7.10 (m, 1H),3.91-3.88 (m, 4H), 3.79-3.76 (m, 2H),3.33-3.23 (m, 2H), 3.17-2.80 (m, 4H), 2.75-2.72 (t, J = 4 Hz, 2H), 1.50-1.95 (m, 7H), 1.18- 1.49 (m, 7H). Synthesis C18: Synthesis of 3-(1-methyl-7-(4-(piperidin-4-ylmethyl)piperidin-1-yl)-1H- indazol-3-yl)piperidine-2,6-dione (C-73):

Step-1: To a stirred solution of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 1 (1 g, 2 mmol) and tert-butyl 4-(4-piperidylmethyl)piperidine-1-carboxylate 2 (733.73 mg, 2.60 mmol) in toluene (15 mL) was added BINAP (373.31 mg, 599.54 μmol) and sodium tert- butoxide (576.16 mg, 6.00 mmol) and the solution was degassed with nitrogen gas for 10 minutes. Tris(dibenzylideneacetone)dipalladium(0) (183.00 mg, 0.199 mmol) was then added and the resulting mixture was heated to stir at 110 °C for 16 hours. The reaction mixture was filtered, washed and concentrated under reduced pressure to get crude product which was purified by flash chromatography (100-200 silica gel) using 30% ethyl acetate in petroleum ether as an eluent to afford tert-butyl 3-((1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol- 7-yl)piperidin-4-yl)methyl)piperidine-1-carboxylate 3 (0.7 g, 43 % yield) as a yellow solid. LCMS (ESI): m/z 702.9 [M+H]⁺. Step-2: To a solution of tert-butyl 3-((1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H- indazol-7-yl)piperidin-4-yl)methyl)piperidine-1-carboxylate 3 (0.5 g, 0.715 mmol) in a mixture of tetrahydrofuran (25 mL) and ethyl acetate (25 mL) was added 10% palladium on carbon (530.66 mg, 4.99 mmol). The resulting reaction mixture was shaken for 16 hours at room temperature under hydrogen atmosphere in parr shaker (60 psi). The reaction mixture was filtered, washed and concentrated under reduced pressure to get crude which was triturated with diethyl ether (20 mL) and pentane (40 mL) to get tert-butyl 4-[[1-[3-(2,6-dioxo-3-piperidyl)-1- methyl-indazol-7-yl]-4-piperidyl]methyl]piperidine-1-carboxylate 4 (0.19 g, 49% yield) as an off white solid. LCMS (ESI): m/z 524.57 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 7.37-7.34 (m, 1H), 7.02-6.99 (m, 2H), 4.34-4.30 (m, 1H), 4.23 (s, 3H), 3.94-3.91 (m, 2H), 3.22-3.20 (m, 2H), 2.71-2.57 (m, 6H), 2.30- 2.29 (m, 1H), 2.17-2.13 (m, 1H), 1.80-1.77 (m, 2H), 1.65-1.62 (m,2H), 1.54-1.51 (m, 2H), 1.39- 1.36 (m, 11 H), 1.23-1.21 (m, 2 H), 1.00-0.94 (m, 2 H) ppm. Step-3: To a stirred solution tert-butyl 4-[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-7-yl]- 4-piperidyl]methyl]piperidine-1-carboxylate 4 (0.1 g, 190.96 μmol) in 1,4 dioaxne (1 mL) was added 4 M HCl in 1,4-dioxane solution (0.4 mL) dropwise at 0 °C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to get crude product which was triturated with diethyl ether (10 mL) to afford 3-[1-methyl-7-[4- (4-piperidylmethyl)-1-piperidyl]indazol-3-yl]piperidine-2,6-dione C-73 (0.095 g, 97 % yield, HCl salt) as off-white solid. LCMS (ESI): m/z 424.60 [M+H]⁺. Synthesis C19: Synthesis of 1-[1-methyl-7-[4-(4-piperidylmethyl)-1-piperidyl]indazol-3- yl]hexahydro-pyrimidine-2,4-dione (C-74): O O BocN NH 3 NH PMB-Cl, Cs₂CO₃ N PMB Pd-PEPPSI-iHeptCl, Cs₂CO N ₃ DMF, RT, 16 h O N 1,4 dioxane, 90 °C, 16 h O N Step-1 Step-2 N N N Br 1 Br 2

Step-1: To a stirred solution of 1-(7-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4- dione 1 (1 g, 3.09 mmol) in N,N-dimethylformamide (10 mL) were added cesium carbonate (3.02 g, 9.28 mmol) and 4-methoxybenzyl chloride (581.57 mg, 3.71 mmol) at 0 °C. The resulting reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was quenched with ice water to get precipitated solid, the solid was then filtered, washed with petroleum ether to afford 1-(7-bromo-1-methyl-indazol-3-yl)-3-[(4- methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione 2 (1.2 g, 84 % yield) as an off-white solid.LC-MS (ES⁺): m/z 445.41 [M+2H]⁺. Step-2: To a stirred solution of 1-(7-bromo-1-methyl-indazol-3-yl)-3-[(4-methoxyphenyl)- methyl]hexahydropyrimidine-2,4-dione 2 (0.5 g, 1.13 mmol) and tert-butyl 4-(4- piperidylmethyl)piperidine-1-carboxylate 3 (382.26 mg, 1.35 mmol) in 1,4-dioxane (2 mL) was added cesium carbonate (918.75 mg, 2.82 mmol), the solution was degassed with nitrogen gas for 5 minutes and then Pd-PEPPSI-iHeptCl (70.23 mg, 0.112 mmol) was added. The reaction mixture was heated to stir at 90 °C for 16 hours and concentrated under reduced pressure to get crude which was purified by column chromatography using (silica gel 100-200 mesh) eluted at 30-40 % ethyl acetate in petroleum ether to afford tert-butyl 4-[[1-[3-[3-[(4- methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]-1-methyl-indazol-7-yl]-4- piperidyl]methyl]piperidine-1-carboxylate 4 (0.3 g, 35% yield) as a pale yellow solid.LC-MS (ES⁺): m/z 645.90 [M+H]⁺. Step-3: To a stirred solution of tert-butyl 4-[[1-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo- hexahydropyrimidin-1-yl]-1-methyl-indazol-7-yl]-4-piperidyl]methyl]piperidine-1-carboxylate 4 (0.3 g, 0.465 mmol) in dichloromethane (3 mL) was added a mixture of trifluoromethanesulfonic acid (0.82 mL, 9.31 mmol,) and trifluoroacetic acid (0.35 mL, 4.65 mmol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to get the crude which was triturated with diethyl ether to afford 1-[1-methyl-7-[4-(4-piperidylmethyl)-1-piperidyl]indazol-3- yl]hexahydropyrimidine-2,4-dione C-74 (0.2 g, 78% yield, TFA salt) as an off white solid. LCMS (ES⁺): m/z 425.46 [M+H] ⁺. ¹ H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 8.41 (s, 1H), 8.14 (s, 1H), 7.27 (t, J = 3.60 Hz, 1H), 7.00 (t, J = 7.60 Hz, 2H), 4.23 (s, 3H), 3.88 (t, J = 6.80 Hz, 2H), 3.30-3.20 (m, 4H), 2.90-2.80 (m, 2H), 0.00 (dd, J = 12.40, Hz, 4H), 1.69 (s, 1H), 1.51 (s, 1H), 1.50- ( ) ( ) Synthesis C20: Synthesis of tert-butyl 4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro- phenyl]-1-piperidyl]ethyl]piperidine-1-carboxylate (C-107) Step-1: To a stirred solution of 1-bromo-2-fluoro-4-nitro-benzene 1 (5 g, 22.73 mmol,) and tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate 2 (7.03 g, 22.73 mmol) in a mixture of water (5 mL) and 1,4-dioxane (50 mL) was added potassium phosphate (12.06 g, 56.82 mmol). The reaction mixture was degassed with nitrogen gas for 5 minutes and Pd(dppf)Cl2· dichloromethane (831.49 mg, 1.14 mmol) was added, and it was heated to stir at 90 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to get crude which was purified by column chromatography using (100-200 silica mesh)10-20 % ethyl acetate in pet ether as an eluent to afford tert-butyl 4-(2-fluoro-4-nitro- phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate 3 (6 g, 68% yield) as a yellow solid. LC-MS (ES-): m/z 321.29 [M-H]-. Step-2: To a solution of tert-butyl 4-(2-fluoro-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1- carboxylate 3 (4 g, 12.41 mmol) in a mixture of tetrahydrofuran (50 mL) and ethyl acetate (50 mL).10% palladium on carbon (4g, 37.59 mmol, 50% wet) was added and the resulting reaction mixture was shaken under hydrogen atmosphere (30 psi) using par shaker for 5 hours. The reaction mixture was filtered through celite pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to get the crude product, which was triturated with petroleum ether to afford tert-butyl 4-(4-amino-2-fluoro-phenyl) piperidine-1-carboxylate 4 (3 g, 73% yield) as an off white solid. LC-MS (ES⁺): m/z 239.27[M-tBu]⁺. Step-3: To a stirred solution of tert-butyl 4-(4-amino-2-fluoro-phenyl) piperidine-1-carboxylate 4 (3 g, 10.19 mmol) in dimethylformamide (30 mL) were added sodium bicarbonate (4.28 g, 50.96 mmol) and 3-bromopiperidine-2,6-dione 5 (9.78 g, 50.96 mmol). The resulting reaction mixture was heated to stir at 70 °C for 16 hours. The reaction mixture was quenched with ice water to get precipitated solid which was filtered off and washed with petroleum ether to afford tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate 6 (2.6 g, 52% yield) as an off white solid. LC-MS (ES⁺): m/z 306.39 [M-Boc]⁺. Step-4: To a stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro- phenyl]piperidine-1-carboxylate 6 (1.5 g, 3.70 mmol) in dichloromethane (5 mL) was added 4 M HCl in 1,4-dioxane (9 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to get the crude which was triturated with diethyl ether to afford 3-[3-fluoro-4-(4- piperidyl)aniline]piperidine-2,6-dione 7 (1.2 g, 81% yield, HCl salt) as an off white solid. LC- MS (ES⁺): m/z 306.39[M+H]⁺. Step-5: To a stirred solution of 3-[3-fluoro-4-(4-piperidyl)aniline]piperidine-2,6-dione 7 (1 g, 2.93 mmol, HCl salt) and tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate 8 (997.49 mg, 4.39 mmol) in tetrahydrofuran (4 mL) were added triethylamine (1.22 mL, 8.78 mmol).The resulting reaction mixture was heated to stir at 70 °C for 16 hours. The reaction was allowed to cool at room temperature. Then sodium cyanoborohydride (551.56 mg, 8.78 mmol) was added and stirred for 2 hours. The reaction mixture was filtered, washed, and the filtrate was concentrated under vacuum to get crude which was purified by reverse phase C18 column, eluted at 20-25% acetonitrile in water to afford tert-butyl 4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro- phenyl]-1-piperidyl]ethyl]piperidine-1-carboxylate C-107 (0.55 g, 35% yield) as an off-white solid). LC-MS (ES⁺): m/z 517.45[M+H]⁺.¹H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 6.98 (t, J = 8.40 Hz, 1H), 6.53 (s, 1H), 6.50-6.40 (m, 2H), 6.01 (d, J = 7.60 Hz, 1H), 4.35-4.25 (m, 1H), 3.90 (d, J = 12.00 Hz, 2H), 3.03 (d, J = 10.00 Hz, 2H), 2.90-2.80 (m, 1H), 2.80-2.50 (m, 5H), 2.50-2.40 (m, 2H), 2.20-2.00 (m, 3H), 1.90-1.80 (m, 1H), 1.70-1.60 (m, 6H), 1.50-1.35 (m, 12H), 1.12 (t, J = 7.20 Hz, 2H), 1.05-0.95 (m, 2H). Synthesis C21: Synthesis of tert-butyl 9-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (C-108) O N O O Pd/C, H HN ₂ (30Psi), 2 N O EtOAc:THF (1:1), RT, 5 h O₂N DIPEA, DMSO,100 °C, 6 h N Step-2 F Step-1 O 3 1 ₂N Step-1: To a stirred solution of 1-fluoro-4-nitro-benzene 1 (0.5 g, 3.54 mmol) and tert-butyl 3,9- diazaspiro[5.5]undecane-3-carboxylate 2 (1.08 g, 4.25 mmol) in dimethyl sulfoxide (8 mL) was added diisopropylethylamine (1.37 g, 10.63 mmol, 1.85 mL) and the resulting mixture was heated to stir at 100 °C for 6 hours. The reaction mixture was quenched with ice water. The precipitated solid was filtered, dried under vacuum to get tert-butyl 9-(4-nitrophenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate 3 (1.2 g, 87 % yield) as a yellow solid. LCMS (ESI): m/z 376.47 [M+H]⁺. Step-2: To a stirred solution of tert-butyl 9-(4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate 3 (1.2 g, 3.20 mmol) in a mixture of tetrahydrofuran (25 mL) and ethyl acetate (25 mL) was added 10% palladium on carbon wet (900 mg, 8.46 mmol). The resulting reaction mixture was shaken for 5 hours at room temperature under hydrogen atmosphere (1 atm) in Parr shaker. The reaction mixture was filtered, washed with ethyl acetate and the filtrate was concentrated under reduced pressure to get crude which was triturated with pentane to afford tert-butyl 9-(4-aminophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate 4 (1 g, 87% yield) as an off white solid. LC-MS (ESI): m/z 346.51 [M+H]⁺. Step-3: To a stirred solution of tert-butyl 9-(4-aminophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate 4 (800 mg, 2.32 mmol) in N,N-dimethylformamide (8 mL) were added sodium bicarbonate (972.64 mg, 11.58 mmol) and 3-bromopiperidine-2,6-dione 5 (2.22 g, 11.58 mmol) portionwise. The resulting reaction mixture was heated to stir at 70 °C for 16 hours. The reaction mixture was quenched with ice water to get solid which was filtered, washed with petroleum ether to get crude compound which was purified by flash chromatography to afford tert-butyl 9- [4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate C-108 (450 mg, 36% yield) as an off white solid. LCMS (ESI): m/z 457.51 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H), 6.76-6.74 (d, J = 9.6 Hz, 2H), 6.60-6.58 (d, J = 8.8 Hz, 2H), 5.34-5.33 (d, J = 7.2 Hz, 1H), 4.19-4.16 (m, 1H), 6.66 (s, 1H), 3.33-2.92 (m, 1H), 2.95-2.85 (m, 4H), 2.80-2.65 (m, 1H), 2.60-2.55 (m, 1H), 2.12-2.08 (m, 1H), 1.85-1.81 (m, 1H), 1.56-4.54 (m, 4H), 1.39-1.36 (m, 13H). Synthesis C22: Synthesis of 3-(6-([1,4'-bipiperidin]-4-yl)benzo[d]isoxazol-3-yl)piperidine- 2,6-dione (C-109)

Step-1: A stirred solution of tert-butyl 4-[3-(2, 6-dioxo-3-piperidyl)-1,2-benzoxazol-6- yl]piperidine-1-carboxylate 1 (1.5 g, 3.63 mmol) in 1,4-dioxane (10 mL) was cooled to 0 °C, then 4M HCl in 1,4-dioxane (15 mL) was added over a period of 10 minutes. The resulting reaction mixture was allowed to stir at room temperature for 5 hours. The reaction was concentrated under reduced pressure to get crude, which was triturated with diethyl ether to afford 3-[6-(4-piperidyl)-1,2-benzoxazol-3-yl]piperidine-2,6-dione 2 (1.1 g, 67% yield, HCl salt) as an off-white solid. LC-MS (ES⁺): m/z 414.34 [M+H] ⁺. Step-2: To a stirred solution of 3-[6-(4-piperidyl)-1, 2-benzoxazol-3-yl] piperidine-2, 6-dione 2 (0.4 g, 1.14 mmol, HCl salt) and tert-butyl 4-oxopiperidine-1-carboxylate 3 (273.40 mg, 1.37 mmol) in tetrahydrofuran (7 mL) was added triethylamine (0.478 mL, 3.43 mmol) and the reaction mixture was heated to stir at 70 °C for 16 hours and then cooled to 0 °C. Sodium cyanoborohydride (143.72 mg, 2.29 mmol) was added and the resulting reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude which was purified by reverse phase purification using 20-25% acetonitrile in water to afford tert-butyl 4-[4-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-6-yl]-1- piperidyl]piperidine-1-carboxylate 4 (0.25 g, 39% yield) as a pale yellow solid. LC-MS (ES⁺): m/z 497.46[M+H]⁺.¹H NMR (400 MHz, DMSO-d6): 11.08 (s, 1H), 7.74 (d, J = 8.00 Hz, 1H), 7.60 (s, 1H), 7.31 (d, J = 7.60 Hz, 1H), 4.55 (dd, J = 4.80, 11.80 Hz, 1H), 3.98 (d, J = 11.20 Hz, 2H), 2.97 (d, J = 11.20 Hz, 2H), 2.85-2.60 (m, 5H), 2.50-2.40 (m, 2H), 2.20-2.15 (m, 1H), 1.90- 1.60 (m, 6H), 1.50-1.30 (m, 11H). Step-3: To a stirred solution of tert-butyl 4-[4-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-6-yl]- 1-piperidyl]piperidine-1-carboxylate 4 (150 mg, 302.06 μmol) in dichloromethane (2 mL) was added HCl (4.0 M i 14 di ) (1101 30206 l) t 0 ℃. The resulting reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was evaporated to get the crude which after diethyl ether wash afforded 3-[6-[1-(4-piperidyl)-4-piperidyl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione 5 (130 mg, 231.36 μmol, 76.59% yield, 77.05% purity, hydrochloric acid) as white solid. LCMS (ES+): m/z 397.55[M+H]⁺. Synthesis C23: Synthesis of tert-butyl 9-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-7-yl]- 3,9-diazaspiro[5.5]undecane-3-carboxylate (C-110) Step-1: To a stirred solution of ethyl 2-(7-bromo-1,2-benzoxazol-3-yl)acetate 1 (400 mg, 1.41 mmol) in toluene (4 mL) was added tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate 2 (537.20 mg, 2.11 mmol) and potassium carbonate (486.46 mg, 3.52 mmol). The reaction mixture was degassed with nitrogen for 5 minutes. Pd-PEPPSI-iHeptCl (205.65 mg, 0.21 mmol) and the resulting reaction mixture was heated to stir at 120 °C for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and then evaporated under reduced pressure to get crude which was purified by flash column chromatography to afford tert- butyl 9-[3-(2-ethoxy-2-oxo-ethyl)-1,2-benzoxazol-7-yl]-3,9-diazaspiro[5.5]undecane-3- carboxylate 3 (80 mg, 41% yield) as a brown thick liquid. LCMS (ESI): m/z 458.54 [M+H]⁺. Step-2: To a stirred solution of tert-butyl 9-[3-(2-ethoxy-2-oxo-ethyl)-1,2-benzoxazol-7-yl]-3,9- diazaspiro[5.5]undecane-3-carboxylate 3 (100 mg, 218.55 μmol) in tetrahydrofuran (2 mL) was added KOtBu (24.52 mg, 218.55 μmol) and prop-2-enamide 4 (15.53 mg, 218.55 μmol) at 0 °C and stirred for 30 minutes. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (2 × 20 mL) to afford crude product, which was purified by flash column chromatography to afford tert-butyl 9-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-7-yl]- 3,9-diazaspiro[5.5]undecane-3-carboxylate 5 (55 mg, 49% yield) as a pale yellow solid. LCMS (ESI): m/z 483.51 [M+H]⁺.¹H-NMR (400 MHz, DMSO-d6): δ 11.1 (s, 1H), 7.26–7.20 (m, 2H), 7.01–6.99 (m, 1H), 4.55 (dd, J = 6.8, 12 Hz, 1H), 3.34–3.29 (m, 8H), 2.78–2.75 (m, 1H), 2.65– 2.60 (s, 2H), 2.47–2.41 (m, 1H), 2.20–2.16 (m, 1H), 1.66–1.64 (m, 4H), 1.46–1.43 (m, 3H), 1.40 (s, 9H). Step-3: To a stirred solution of tert-butyl 9-[3-(2,6-dioxo-3-piperidyl)-1,2-benzoxazol-7-yl]-3,9- diazaspiro[5.5]undecane-3-carboxylate 5 (200 mg, 414.45 μmol) in dichloromethane (2 mL) was added HCl (4.0 M in 1,4-dioxane) (15.11 mg, 414.45 μmol, 0.2 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to get crude product which was triturated with diethyl ether (2 x 1 mL) to afford 3-[7-(3,9-diazaspiro[5.5]undecan-3-yl)-1,2-benzoxazol-3-yl]piperidine-2,6- dione 6 (170 mg, 359.79 μmol, 86.81% yield, 88.66% purity, hydrochloric acid) as an off white solid. LCMS (ES+): m/z 383.91 [M+H]⁺. EXAMPLE 4: SYNTHESIS OF THE FINAL DEGRADER COMPOUNDS Synthesis 1: Synthesis of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-N- [[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2S,8R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3- piperidyl]methyl]acetamide (Compound 1): To a stirred solution of 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)acetic acid (C-17) (59.78 mg, 173.07 μmol) and 4-(4-(3-(aminomethyl)piperidin-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (A-2) (70 mg, 115.38 μmol, 061) in N,N- dimethylformamide (1 mL) was added DIPEA (44.74 mg, 3.7 mmol, 649.27 μL), followed by HATU (87.74 mg, 230.76 μmol) at room temperature. The reaction mixture was stirred at 25 °C for two hours. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford crude product (80 mg). The resulting crude was purified by prep- HPLC to afford 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-N-[[1-[7-(8-ethyl- 7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2S,8R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-piperidyl]methyl]acetamide (Compound 1) (8.2 mg, 8.40 μmol, 7.28% yield, 95.71% purity) as white solid. Prep. HPLC condition: Column/dimensions: Acquity UPLC BEH C18, 1.7 μm (50 mm x 2.1 mm); Mobile phase A: 0.1 % FA in water; Mobile phase B: 100% acetonitrile (Org); Gradient (Time/%B): 0/3, 1.0/3, 7.0/95, 7.5/95, 9.0/3, 10/3; Flow rate: 0.5 mL/min; Solubility: Acetonitrile+THF+Water; Spot visualization: UV active compound; LCMS (ES⁺): m/z 934.62 [M+H]⁺; Retention time (min): 1.32; ¹H NMR (400 MHz, DMSO-d6): δ 11.20 (bs, 1H), 8.98 (d, J = 3.6 Hz, 1H), 7.95 (t, J = 5.6 Hz, 1H), 7.69 (t, J = 7.2 Hz, 1H), 7.32–7.26 (m, 2H), 6.99 (s, 1H), 6.91–6.88 (m, 2H), 6.57 (d, J = 7.6 Hz, 2H), 5.62 (d, J = 7.6 Hz, 1H), 5.36–5.19 (m, 1H), 4.44 (bs, 2H), 4.24 (d, J = 3.6 Hz, 1H), 4.15 (bs, 1H), 4.08–3.94 (m, 1H), 3.22–2.68 (m, 12H), 2.58 (m, 1H), 2.41–1.93 (m, 10H), 1.90–1.52 (m, 13H), 1.39 (bs, 1H), 0.79 (t, J = 3.6 Hz, 3H). Synthesis 2: Synthesis of 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-N- [[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-piperidyl]methyl]-4- oxo-butanamide (Compound 2): To a stirred solution of 4-[4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoro-naphthalen-2-ol (A-2) (80 mg, 131.87 μmol) in N,N-dimethylformamide (1 mL) was added HATU (55.15 mg, 145.05 μmol) and DIPEA (51.13 mg, 395.60 μmol, 68.90 μL) followed by the addition 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-4-oxo-butanoic acid (C-1) (35.76 mg, 92.31 μmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water (10 mL) and directly kept for lyophilization to afford crude product (110 mg). The resulting crude was purified by prep. HPLC to afford 4-[4-[4-[(2,6-dioxo- 3-piperidyl)amino]phenyl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-3-piperidyl]methyl]-4-oxo-butanamide (Compound 2) (21.3 mg, 20.81 μmol, 15.78% yield, 95.36% purity) as a white solid. Prep. HPLC condition: Column/dimensions: KINETEX C18; Mobile phase A: 5 mM ammonium acetate in water (aq); Mobile phase B: acetonitrile; Gradient (Time/%B): 0/35, 2/35, 10/63, 13/63, 13.01/100, 16/100, 16.01/35, 18/35; Flow rate: 18mL/min; Solubility: H2O+CAN; Spot visualization: UV active compound; LCMS (ES⁺): m/z 976.70 [M+H]⁺; Retention time (min): 1.54; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (bs, 1H), 10.20 (bs, 1H), 8.99 (d, J = 8.8 Hz, 1H), 8.08–7.99 (bs, 1H), 7.75 (bs, 1H), 7.38–7.28 (m, 2H), 7.03 (s, 1H), 6.94–6.87 (m, 2H), 6.59 (d, J = 2.4 Hz, 2H), 5.66 (d, J = 7.2, 1H), 5.36– 5.21 (m, 1H), 4.45 (t, J = 7.2 Hz, 3H), 4.27 (t, J = 5.6 Hz, 1H), 4.15 (d, J = 7.8 Hz, 1H), 4.07 (d, J = 7.8 Hz, 1H), 4.03 (bs, 2H), 3.84 (m, 1H), 3.24–2.66 (m, 10H), 2.48 (m, 2H), 2.33 (s, 3H), 2.23–1.58 (m, 15H), 1.47–1.27 (m, 4H), 0.71 (t, J = 6.8 Hz, 3H). Synthesis 3: Synthesis of 7-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)- N-((1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-yl)methyl)-7-oxoheptanamide (Compound 3):

To a stirred solution of 7-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)- 7-oxoheptanoic acid (C-2) (74.34 mg, 173.07 μmol) and 4-(4-(3-(aminomethyl)piperidin-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (A-2) (70 mg, 115.38 μmol, 061) in N,N- dimethylformamide (1 mL)was added DIPEA (44.74 mg, 3.7 mmol, 649.27 μL) followed by the addition of HATU (87.74 mg, 230.76 μmol) at room temperature. The reaction mixture was stirred at 25 °C for two hours. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford crude product (100 mg). The resulting crude was purified by prep. HPLC and SFC to afford 7-(4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidin-1-yl)-N-((1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-3-yl)methyl)-7-oxoheptanamide (Compound 3) (5 mg, 4.68 μmol, 4.06% yield, 95.40% purity) as yellow solid. Spot visualization: UV active compound; Prep. HPLC condition: Column: X-Bridge C18, 1.7μm (50mmX2.1mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase B: 100% CAN; Gradient (T%B): 0/3, 1.0/3, 7.0/95, 7.5/95, 9.0/3, 10/3; Flow Rate: 0.5mL/min; Solubility: Acetonitrile+THF+Water. After Prep-HPLC purification the obtained compound was further purified by SFC purification. SFC condition: Column/dimensions: ethyl pyridine (30x250) mm, 5μ% CO2: 50%, % Co solvent: 50% ( ACN:IPA )(1:1), Total Flow: 100 mL/min, Back Pressure: 100 bar, UV:220 nm; LCMS (ES⁺): m/z 1018.71 [M+H]⁺; Retention time (min): 4.99; ¹H NMR (400 MHz, DMSO-d6): δ 11.76 (bs, 1H), 10.01 (bs, 1H), 8.99 (d, J = 1.6 Hz, 1H), 7.95 (t, J = 5.6 Hz, 1H), 7.75 (t, J = 7.2, 2.8 Hz, 1H), 7.36–7.32 (m, 2H), 6.99 (s, 1H), 6.92 (d, J = 7.6 Hz, 2H), 6.57 (d, J = 7.6 Hz, 2H), 5.66 (d, J = 7.6 Hz, 1H), 5.36–5.19 (m, 1H), 4.54–4.22 (m, 4H), 4.18 (d, J = 7.6 Hz, 1H), 4.08 (d, J = 7.6 Hz, 1H), 3.88–3.72 (m, 1H), 3.23–2.88 (m, 8H), 2.84–2.53 (m, 4H), 2.33 (s, 1H), 2.23–1.93 (m, 9H), 1.91–1.61 (m, 9H), 1.53–1.15 (m, 8H), 1.03 (d, J = 7.6 Hz, 3H), 0.79 (t, J = 3.6 Hz, 3H). Synthesis 4: Synthesis of 10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-N- [[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-piperidyl]methyl]-10- oxo-decanamide (Compound 4): To a stirred solution of 10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-10- oxo-decanoic acid (C-3) (81.62 mg, 173.07 μmol) in N,N-dimethylformamide (0.7 mL) at 0 °C was added DIPEA (44.74 mg, 346.15 μmol, 60.29 μL) followed by HATU (87.74 mg, 230.76 μmol). After 10 minutes 4-[4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6-fluoro- naphthalen-2-ol (A-2) (70 mg, 115.38 μmol) was added. Then the reaction mixture was stirred at room temperature for two hours. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic layer was dried over sodium sulphate,filtered, and concentrated under reduced pressure to afford crude product (90 mg). The resulting crude was purified by prep. HPLC to afford 10-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-3-piperidyl]methyl]-10-oxo-decanamide (Compound 4) (6.3 mg, 5.65 μmol, 4.89% yield, 95.02% purity) as an off-white solid. Prep. HPLC condition: Column: X-Bridge C18; 5u (4.6mm*150mm); Mobile Phase A: 10 mM ammonium acetate in water; Mobile Phase B: 100% acetonitrile; Gradient (T%B): 0/10, 8/95, 11/95.12/10, 15/10; Flow Rate: 1.0 mL/min; Sample Diluent: ACN+Water; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1060.76 [M+H]⁺; Retention time (min): 1.68; ¹H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 10.61 (s, 1H), 9.98 (s, 1H), 9.05 (d, J = 2.8 Hz, 1H), 7.96 (t, J = 5.6 Hz, 1H), 7.86–7.74 (m, 1H), 7.37–7.33 (m, 2H), 7.01–6.99 (dd, J = 7.2, 2.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 5.66 (d, J = 7.4 Hz, 1H), 5.52 (bs, 1H), 4.70–4.36 (m, 5H), 4.24 (bs, 1H), 3.97–3.62 (bs, 4H), 3.38–2.95 (m, 7H), 2.79–2.53 (m, 3H), 2.39–2.22 (m, 3H), 2.16–1.81 (m, 11H), 1.79– 1.54 (bs, 4H), 1.53–1.22 (m, 8H), 1.19–1.08 (m, 8H), 0.72 (t, J = 7.2 Hz, 3H). Synthesis 5: Synthesis of 12-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)- N-((1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-yl)methyl)-12-oxododecanamide (Compound 5):

To a stirred solution of 12-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)-12-oxododecanoic acid (C-4) (86.47 mg, 173.07 μmol) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (44.74 mg, 346.15 μmol, 60.29 μL) followed by HATU (87.74 mg, 230.76 μmol). After 10 minutes, 4-[4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoro-naphthalen-2-ol (A-2) (70 mg, 115.38 μmol) was added. Then reaction mixture was stirred at 25 °C for two hours. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford crude product (100 mg). The resulting crude was purified by prep. HPLC to afford 12-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-N-((1-(7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methyl)-12- oxododecanamide (Compound 5) (8.88 mg, 7.80 μmol, 6.76% yield, 95.55% purity) as white solid. Prep. HPLC condition: Column: UPLC BEH C18, 1.7 μm (50 mm x 2.1 mm); Mobile Phase A: 0.1% formic acid in water; Mobile Phase B: 100% acetonitrile; Gradient (T%B): 0/3, 1.0/3, 7.0/95, 7.5/95, 9.0/3, 10/3; Flow Rate: 0.5 mL/min; Sample Diluent: ACN+Water; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1088.83 [M+H]⁺; Retention time (min): 1.78; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (bs, 1H), 8.98 (d, J = 2.4 Hz, 1H), 7.94 (t, J = 5.6 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.32–7.25 (m, 2H), 6.99 (s, 1H), 6.93–6.91 (m, 2H), 6.59 (d, J = 8.8 Hz, 2H), 5.65 (d, J = 7.2 Hz, 1H), 5.36–5.19 (m, 1H), 4.57–4.34 (m, 3H), 4.27 (bs, 1H), 4.18–4.04 (m, 2H), 3.87 (d, J = 8.4 Hz, 1H), 3.21–2.96 (m, 8H), 2.86–2.55 (m, 4H), 2.38– 2.21 (m, 3H), 2.18–1.94 (m, 7H), 1.89–1.62 (m, 11H), 1.48–1.37 (m, 8H), 1.34–1.06 (m, 12H), 0.73 (t, J = 7.2 Hz, 3H). Synthesis 6: Synthesis of 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-N-((1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methyl)acetamide (Compound 6): O N N O N O ^O _H N N H F N Et N N N O F N OH Compound 6 F To a stirred solution of 4-[4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoro-naphthalen-2-ol (A-2) (50 mg, 82.42 μmol) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-3- methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetic acid (C-21) (33.00 mg, 82.42 μmol) in N,N-dimethylformamide (1 mL) was added DIPEA (10.65 mg, 82.42 μmol, 14.36 μL) followed by the addition of HATU (31.34 mg, 82.42 μmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford crude product (100 mg). The resulting crude was purified b HPLC ff d 2 [4 [1 (26 di 3 iperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-3-piperidyl]methyl]acetamide (Compound 6) (10 mg, 9.61 μmol, 11.66% yield, 95.05% purity) as a white solid. Prep HPLC condition: Column/dimensions: X-BRIDGE C-18; Mobile phase A: 5 mM ammonium bicarbonate in water; Mobile phase B: acetonitrile; Gradient (Time/%B): 0/25,2/25,12/58,14/58,14.1/100,17.0/100,17.1/25,20/25; Flow rate: 18 mL/min; Solubility: H2O+ACN; Spot visualization: UV active compound; LCMS (ES⁺): m/z 989.60 [M+H]⁺; Retention time (min): 4.97; ¹H NMR (400 MHz, DMSO-d6): δ 11.11 (bs, 1H), 8.98 (d, J = 2.4 Hz, 1H), 7.97 (t, J = 5.6 Hz, 1H), 7.74–7.70 (m, 1H), 7.34–7.28 (m, 2H), 7.08 (s, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H), 5.37–5.16 (m, 2H), 4.47 (q, J = 8.8, 4.4 Hz, 2H), 4.13 (d, J = 7.2 Hz, 1H), 4.03 (d, J = 7.2 Hz, 1H), 3.34 (bs, 4H), 3.22–2.77 (m, 12H), 2.75– 2.52 (m, 2H), 2.38 (bs, 2H), 2.17–1.93 (m, 8H), 1.91–1.53 (m, 11H), 1.38 (bs, 1H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 7: Synthesis of 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3- piperidyl]methyl]-4-oxo-butanamide (Compound 7):

To a stirred solution of 4-[4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoro-naphthalen-2-ol (A-2) (50 mg, 82.42 μmol) and 4-[4-[1-(2,6-dioxo-3-piperidyl)-3- methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-4-oxo-butanoic acid (C-5) (29.17 mg, 65.94 μmol) in N,N-dimethylformamide (971.33 μL) was added DIPEA (31.96 mg, 247.26 μmol, 43.07 μL) followed by the addition of HATU (47.01 mg, 123.63 μmol) at room temperature. The reaction mixture was stirred at room temperature for an hour. The progress of the reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with water (5 mL) and directly kept for lyophilization to afford crude product (90 mg). The resulting crude was purified by prep. HPLC to afford 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl- 2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-3-piperidyl]methyl]-4-oxo-butanamide (Compound 7) (6 mg, 5.44 μmol, 6.61% yield, 93.57% purity) as a white solid. Prep HPLC condition: Column/dimensions: X- BRIDGE C-18; Mobile phase A: 5 mM ammonium bicarbonate in water; Mobile phase B: acetonitrile; Gradient (Time/%B): 0/25, 2/25, 12/58, 14/58, 14.1/100, 17.0/100, 17.1/25, 20/25; Flow rate: 18mL/min; Solubility: H₂O+ACN; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1031.67 [M+H]⁺; Retention time (min): 4.82; ¹H NMR (400 MHz, DMSO-d6): δ 11.13–1.66 (bs, 2H), 8.99 (d, J = 3.2 Hz, 1H), 7.98 (t, J = 5.6 Hz, 1H), 7.75–7.71 (m, 1H), 7.36– 7.30 (m, 2H), 7.08–6.99 (m, 3H), 6.89 (d, J = 2.4 Hz, 1H), 5.39–5.19 (m, 2H), 4.54–4.38 (bs, 3H), 4.18 (d, J = 8.0 Hz, 1H), 4.09 (d, J = 8.0 Hz, 1H), 3.85 (bs, 1H), 3.26–2.56 (m, 14H), 2.39– 1.93 (m, 9H), 1.89–1.58 (m, 10H), 1.56–1.33 (m, 6H), 0.72 (t, J = 7.2 Hz, 3H). Synthesis 8: Synthesis of 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3- piperidyl]methyl]-6-oxo-hexanamide (Compound 8): To a stirred solution of 4-[4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoro-naphthalen-2-ol (A-2) (80 mg, 131.87 μmol) in N,N-dimethylformamide (1 mL) was added 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-6-oxo- hexanoic acid (C-6) (37.23 mg, 79.12 μmol) and DIPEA (51.13 mg, 395.60 μmol, 68.90 μL) followed by the addition of HATU (55.15 mg, 145.05 μmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with water (10 mL) and directly kept for lyophilization to afford crude product (110 mg). The resulting crude was purified by prep. HPLC to afford 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-3-piperidyl]methyl]-6-oxo-hexanamide (Compound 8) (25.5 mg, 22.89 μmol, 17.36% yield, 95.06% purity) as a white solid. Prep HPLC condition: Column/dimensions: X-BRIDGE- SELECT-(19*250mm*5μ); Mobile phase A: 10 mM ammonium acetate in water (aq); Mobile phase B: acetonitrile; Gradient (Time/%B): 0/10,2/10,8/55,14/55,14.01/98,18/98,18.01/10,20/10; Flow rate: 18 mlL/min; Solubility: THF+H₂O+ACN; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1059.68 [M+H]⁺; Retention time (min): 1.52; ¹H NMR (400 MHz, DMSO-d6): δ 11.13 (bs, 1H), 10.09 (bs, 1H), 8.99 (d, J = 3.2 Hz, 1H), 7.97 (t, J = 5.6 Hz, 1H), 7.77–7.73 (m, 1H), 7.36–7.30 (m, 2H), 7.08 (s, 1H), 7.02–6.99 (m, 2H), 6.89 (d, J = 2.4 Hz, 1H), 5.39–5.19 (m, 2H), 4.56 (d, J = 7.2 Hz, 1H), 4.50–4.32 (m, 2H), 4.18 (d, J = 8.0 Hz, 1H), 4.09 (d, J = 8.0 Hz, 1H), 3.85 (bs, 1H), 3.26– 2.56 (m, 16H), 2.39–1.93 (m, 10H), 1.89–1.58 (m, 10H), 1.56–1.33 (m, 7H), 0.72 (t, J = 7.2 Hz, 3H). Synthesis 9: Synthesis of 10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3- piperidyl]methyl]-10-oxo-decanamide (Compound 9):

To a stirred solution of 10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-1-piperidyl]-10-oxo-decanoic acid (C-7) (52.08 mg, 98.90 μmol) and 4-[4-[3- (aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6-fluoro-naphthalen-2-ol (A-2) (0.050 g, 82.42 μmol) in N,N-dimethylformamide (1 mL) was added DIPEA (53.26 mg, 412.08 μmol, 71.78 μL), followed by the addition of HATU (62.67 mg, 164.83 μmol) at room temperature. The reaction mixture was stirred at room temperature for two hours. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with cold water (10 mL) and stirred variously, solid precipitate out which was filtered under reduced pressure to obtain crude product (100 mg). The resulting crude was purified by prep. HPLC to afford 10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-[[1- [7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-piperidyl]methyl]-10-oxo- decanamide (Compound 9) (7 mg, 6.08 μmol, 7.38% yield, 96.85% purity) as white solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18; Mobile phase A: 5 mM ammonium bicarbonate in water; Mobile phase B: 100% acetonitrile (Org); Gradient (Time/%B): 0/25,2/25,10/50,16/50,16.1/100,19.0/100,19.1/25,21/25. Flow rate: 18 mL/min; Solubility: Acetonitrile+THF+Water. Spot visualization: UV active compound; LCMS (ES⁺): m/z 1115.83 [M+H]⁺; Retention time (min): 5.09; ¹H NMR (400 MHz, DMSO-d6): δ 11.26 (bs, 1H), 8.98 (d, J = 3.2 Hz, 1H), 8.54 (s, 1H), 7.95 (t, J = 5.6 Hz, 1H), 7.74–7.71 (m, 1H), 7.34–7.29 (m, 2H), 7.08 (s, 1H), 6.99 (d, J = 7.6 Hz, 2H), 6.89 (d, J = 8.0 Hz, 1H), 5.39–5.19 (m, 2H), 4.56 (d, J = 7.2 Hz, 1H), 4.50–4.32 (m, 2H), 4.27 (t, J = 7.2 Hz, 2H), 4.18 (d, J = 8.0 Hz, 1H), 4.09 (d, J = 8.0 Hz, 1H), 3.33–2.93 (m, 11H), 2.88–2.54 (m, 5H), 2.34 (s, 1H), 2.26 (bs, 2H), 2.17–1.90 (m, 8H), 1.86–1.71 (m 8H) 161 137 (m 8H) 121 108 (bs 8H) 069 (t, J = 7.2 Hz, 3H). Synthesis 10: Synthesis of 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3- piperidyl]methyl]acetamide (Compound 10): To a stirred solution of 4-[4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoro-naphthalen-2-ol (A-2) (65 mg, 107.14 μmol) in N,N-dimethylformamide (1 mL) was added DIPEA (27.69 mg, 214.28 μmol, 37.32 μL) and HATU (48.89 mg, 128.57 μmol) followed by the addition of 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1- piperidyl]acetic acid (C-22) (30.03 mg, 75.00 μmol) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water (5 mL) and directly kept for lyophilization for the evaporation of N,N-dimethylformamide. The resulting crude was purified by prep. HPLC to afford 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1- piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3- piperidyl]methyl]acetamide (Compound 10) (20.6 mg, 20.35 μmol, 18.99% yield, 97.70% purity) as a white solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18 (19*150, 5μm); Mobile phase A: 10 mM ammonium acetate in water (aq); Mobile phase B: acetonitrile; Gradient (Time/%B) :0/30, 2/30, 12/48, 15/48, 15.01/98, 18.0/98, 18.01/30, 21/30; Flow rate: 17 mL/min; Solubility: THF+H2O+ACN; LCMS (ES⁺): m/z 989.66 [M+H]⁺; Retention time (min): 1.38; ¹H NMR (400 MHz, DMSO-d6): δ 11.23 (bs, 1H), 8.98 (s, 1H), 8.01 (t, J = 5.6 Hz, 1H), 7.73–7.67 (m, 1H), 7.32–7.28 (m, 2H), 7.01 (s, 1H), 7.0–6.96 (m, 3H), 5.43–5.22 (m, 2H), 4.53–4.37 (m, 2H), 4.18 (d, J = 8.0 Hz, 1H), 4.09 (d, J = 8.0 Hz, 1H), 3.53 (m, 4H), 3.19–2.76 (m, 14H), 2.70–2.58 (m, 2H), 2.36 (bs, 1H), 2.24–1.96 (m, 9H), 1.92–1.64 (m, 8H), 1.39 (bs, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 11: Synthesis of 3-(4-(1-(12-(4-(5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-methyl-1H-pyrazole-3- carbonyl)piperazin-1-yl)-12-oxododecanoyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound 11):

To a stirred solution of 4-[4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoro-naphthalen-2-ol (65 mg, 107.14 μmol) (A-2) was added DIPEA (27.69 mg, 214.28 μmol, 37.32 μL) and HATU (40.74 mg, 107.14 μmol) followed by the addition of 4-[4-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-4-oxo-butanoic acid (C-9) (28.44 mg, 64.28 μmol) at 0 °C. The reaction mixture was stirred at room temperature for 8 hours. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was diluted with water (5 mL) and directly kept for lyophilization for the evaporation N,N- dimethylformamide. The resulting crude was purified by prep. HPLC to afford 4-[4-[1-(2,6- dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-piperidyl]methyl]-4-oxo-butanamide (15.2 mg, 14.27 μmol, 13.32% yield, 96.82% purity) (Compound 11) as a white solid. Prep. HPLC condition: Column/dimensions: GEMINI-NX C18(21*250); Mobile phase A: 0.1% FA in water; Mobile phase B: ACN; Gradient (Time/%B): 0/10,2/10,11.80/51,11.90/98,15/98; Flow rate: 18mL/min; Solubility: H₂O+ACN; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1031.66 [M+H]⁺; Retention time (min): 1.60; ¹H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 10.04 (bs, 1H), 9.02 (bs, 1H), 8.42 (bs, 1H), 8.02 (bs, 1H), 7.74 (bs, 1H), 7.36–7.28 (bs, 2H), 7.03–6.87 (m, 4H), 5.43–5.22 (m, 2H), 4.53–4.39 (bs, 3H), 4.18 (d, J = 8.0 Hz, 1H), 4.09 (d, J = 8.0 Hz, 1H), 3.85 (bs, 1H), 3.62 (s, 3H), 3.27–2.78 (m, 12H), 2.72–2.56 (m, 2H), 2.34 (m, 3H), 2.16–1.58 (m, 16H), 1.40 (bs, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 12: Synthesis of 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3- piperidyl]methyl]-6-oxo-hexanamide (Compound 12): To a stirred solution of 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-1-piperidyl]-6-oxo-hexanoic acid (62.04 mg, 131.87 μmol) (C-10) and 4-[4-[3- (aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6-fluoro-naphthalen-2-ol (A-2) (80 mg, 131.87 μmol) in N,N-dimethylformamide (1 mL) was added DIPEA (51.13 mg, 395.60 μmol, 68.91 μL) followed by the addition of HATU (55.15 mg, 145.05 μmol) at room temperature. The reaction mixture was stirred at 25 °C for 3 hours. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with water (10 mL) and directly kept for lyophilization to afford crude product (120 mg). The resulting crude was purified by prep. HPLC to afford 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-4-yl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-3-piperidyl]methyl]-6-oxo-hexanamide (Compound 12) (10 mg, 8.98 μmol, 6.81% yield, 95.10% purity) as a white solid. Prep. HPLC condition: Column/dimensions: KINETEX C18; Mobile phase A: 5 mM ammonium acetate in water (aq); Mobile phase B: ACN; Gradient (Time/%B): 0/35, 2 35; Flow rate: 18mL/min; Solubility: H₂O+ACN; Spot visualization: UV active compound.; LCMS (ES⁺): m/z 1059.67 [M+H]⁺; Retention time (min): 4.79; ¹H NMR (400 MHz, DMSO-d6): δ 11.23 (bs, 1H), 9.0 (d, J = 3.2 Hz, 1H), 7.97 (t, J = 5.6 Hz, 1H), 7.75–7.71 (m, 1H), 7.34–7.29 (m, 2H), 7.08 (s, 1H), 6.99 (m, 3H), 5.43–5.22 (m, 2H), 4.56 (d, J = 7.2 Hz, 1H), 4.50–4.32 (m, 2H), 4.18 (d, J = 8.0 Hz, 1H), 4.09 (d, J = 8.0 Hz, 1H), 3.85 (bs, 1H), 3.62 (s, 3H), 3.44–3.39 (bs, 4H), 3.19–2.92 (m, 7H), 2.90–2.79 (m, 2H), 2.72–2.56 (m, 2H), 2.38–1.33 (m, 26H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 13: Synthesis of 10-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-N-((1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methyl)-10-oxodecanamide (Compound 13): To a stirred solution of 4-[4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoro-naphthalen-2-ol (A-2) (70 mg, 108.84 μmol, hydrochloric acid) and 10-[4-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-10-oxo-decanoic acid (C-11) (83.67 mg, 130.61 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) was added DIPEA (70.33 mg, 544.20 μmol, 94.79 μL) followed by addition of HATU (82.77 mg, 217.68 μmol) at 0 °C. Re i i i d for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) and stirred for 10 minutes. The obtained solid filtered to afford the crude product (55 mg). The obtained crude was purified by prep HPLC to obtain 10-[4-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-piperidyl]methyl]-10-oxo-decanamide (Compound 13) (7 mg, 6.06 μmol, 5.57% yield, 96.62% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-bridge C18 (19*250*5μ); Mobile phase A: 5 mM ammonium bicarbonate in water; Mobile phase B: ACN (org); Flow rate: 18 mL/min; Gradient (Time/%B): 0/30, 2/30, 10/65, 14/65, 14.10/100, 17/100, 17.10/30, 20/30; Solubility: Acetonitrile+THF+water. Note: For solubility 2 drops of TFA was used. Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1115.75 [M+H]⁺; Retention time (min): 5.24; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 9.92 (s, 1H), 8.99 (d, J = 3.2 Hz, 1H), 7.93 (t, J = 5.6 Hz, 1H), 7.77–7.73 (m, 1H), 7.36–7.31 (m, 2H), 7.08–6.92 (m, 4H), 5.39–5.21 (m, 2H), 4.61–4.37 (m, 3H), 4.18–3.93 (m, 3H), 3.55 (s, 3H), 3.53–3.48 (m, 2H), 3.22–2.96 (m, 8H), 2.76–2.55 (m, 4H), 2.28 (bs, 2H), 2.19–1.88 (m, 7H), 1.83–1.62 (m, 10H), 1.48 (bs, 7H), 1.27 (bs, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 14: Synthesis of 12-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-N-((1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methyl)-12-oxododecanamide (Compound 14):

To a stirred solution of 4-[4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoro-naphthalen-2-ol (A-2) (70 mg, 108.84 μmol, hydrochloric acid) and 12-[4-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-12-oxo-dodecanoic acid (C-12) (87.34 mg, 130.61 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) was added HATU (82.77 mg, 217.68 μmol) followed by addition of DIPEA (70.33 mg, 544.20 μmol, 94.79 μL) at 0 °C. Reaction mixture was stirred at room temperature for two hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) and stirred for 10 minutes. The obtained solid filtered to afford the crude product (55 mg). The crude was purified by prep HPLC to obtain 12-[4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-N-[[1-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-piperidyl]methyl]-12-oxo-dodecanamide (Compound 14) (12 mg, 10.37 μmol, 9.53% yield, 98.84% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: x-bridge C18 (19*250*5μ); Mobile phase A: 5 mM ammonium bicarbonate in water; Mobile phase B: ACN (org); Flow rate: 18 mL/min; Gradient (Time/%B): 0/30,2/30,10/65,14/65,14.10/100,17/100,17.10/30,20/30; Solubility: Acetonitrile+THF+water. Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1143.83 [M+H]⁺; Retention time (min): 1.73; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 9.92 (s, 1H), 8.99 (d, J = 3.2 Hz, 1H), 8.49 (s, 1H), 7.94 (t, J = 5.6 Hz, 1H), 7.77–7.73 (m, 1H), 7.36– 7.31 (m, 2H), 7.08–6.95 (m, 4H), 5.39–5.21 (m, 2H), 4.61–4.37 (m, 3H), 4.18–3.93 (m, 3H), 3.55 (s, 3H), 3.53–3.48 (m, 2H), 3.22–2.96 (m, 8H), 2.78–2.55 (m, 4H), 2.28 (bs, 2H), 2.19– 1.90 (m, 8H), 1.88–1.62 (m, 9H), 1.48 (bs, 5H), 1.37–1.08 (m, 13H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 15: Synthesis of N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-N'-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2S,8R)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3- piperidyl]methyl]pentanediamide (Compound 15): To a stirred solution of 4-[4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoro-naphthalen-2-ol (A-2) (70 mg, 108.84 μmol, hydrochloric acid) and 5-[[1-(2,6-dioxo-3- piperidyl)-2-oxo-benzo[cd]indol-6-yl]methylamino]-5-oxo-pentanoic acid (C-13) (40.95 mg, 76.19 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added HATU (49.66 mg, 130.61 μmol) followed by DIPEA (42.20 mg, 326.52 μmol, 56.87 μL). Then the reaction mixture was stirred at 25 °C for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion the reaction mixture was diluted with water (5 mL) and lyophilized to obtain crude. The crude was purified by prep-HPLC to obtain N-[[1-(2,6-dioxo-3-piperidyl)- 2-oxo-benzo[cd]indol-6-yl]methyl]-N'-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-3-piperidyl]methyl]pentanediamide (Compound 15) (38 mg, 36.45 μmol, 33.49% yield, 97.0 Column: X Bridge C18 5μm (19x250mm); Mobile Phase A: 10 mM ammonium bicarbonate in H₂O; Mobile Phase B: 100% ACN; Gradient (T%B): 0/15, 1/15,10/30,14/30,14.1/100,18/100,18.1/15,20/15; Flow Rate: 17mL/min; Sample Diluent: ACN+Water; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1012.66 [M+H]⁺; Retention time (min): 1.50; ¹H NMR (400 MHz, DMSO- d6): δ 11.11 (bs, 1H), 8.99 (s, 1H), 8.32 (d, J = 8.0 Hz, 2H), 8.08 (d, J = 7.2 Hz, 1H), 7.93 (t, J = 8.0 Hz, 1H), 7.83 (t, J = 8.4 Hz, 1H), 7.76–7.70 (m, 1H), 7.39–7.29 (m, 3H), 7.08 (d, J = 7.2 Hz, 1H), 7.03 (s, 1H), 5.49–5.22 (m, 2H), 4.64 (s, 2H), 4.49–4.33 (m, 2H), 4.17–3.98 (m, 2H), 3.18–2.92 (m, 8H), 2.86–2.64 (m, 3H), 2.33 (bs, 1H), 2.16–1.95 (m, 8H), 1.89–1.64 (m, 11H), 1.33 (bs, 1H), 0.71 (d, J = 7.2 Hz, 3H). Synthesis 16: Synthesis of N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-N'-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2S,8R)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3- piperidyl]methyl]heptanediamide (Compound 16):

To a stirred solution of 4-[4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoro-naphthalen-2-ol (A-2) (70 mg, 108.84 μmol, hydrochloric acid) and 7-[[1-(2,6-dioxo-3- piperidyl)-2-oxo-benzo[cd]indol-6-yl]methylamino]-7-oxo-heptanoic acid (C-14) (43.08 mg, 76.19 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added HATU (45.52 mg, 119.73 μmol) followed by DIPEA (42.20 mg, 326.52 μmol, 56.87 μL). Then reaction mixture was stirred at 25 °C for 8 hours. The reaction progress was monitored by TLC and LCMS. After completion the reaction mixture was diluted with water (5 mL) and lyophilized to obtain crude. The crude was purified by prep-HPLC to obtain N-[[1-(2,6-dioxo-3-piperidyl)-2- oxo-benzo[cd]indol-6-yl]methyl]-N'-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-3-piperidyl]methyl]heptanediamide (Compound 16) (21 mg, 18.43 μmol, 16.93% yield, 95.32% purity, Formic acid) as white solid. Prep. HPLC condition: Column/dimensions: GEMINI-NX C18 (21*250); Mobile phase A: 0.1% FA in water; Mobile phase B: 100% acetonitrile; Gradient (Time/%B): 0/10, 2/15,12/53,12.10/98; Flow rate: 18 mL/min; Solubility: Water+ACN; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1040.60 [M+H]⁺; Retention time (min): 5.56; ¹H NMR (400 MHz, DMSO-d6): δ 11.13 (bs, 1H), 8.99 (s, 1H), 8.33–8.26 (m, 2H), 8.09 (d, J = 6.0 Hz, 1H), 7.92 (t, J = 5.6 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.77–7.72 (m, 1H), 7.39–7.31 (m, 3H), 7.08 (t, J = 7.6 Hz, 1H), 7.02 (s, 1H), 5.49–5.22 (m, 2H), 4.68 (d, J = 5.6 Hz, 2H), 4.47–4.33 (bs, 2H), 4.17–3.99 (m, 2H), 3.16–2.92 (m, 8H), 2.86–2.62 (m, 3H), 2.33 (s, 1H), 2.16–1.93 (m, 9H), 1.91–1.68 (m, 7H), 1.52–1.33 (m, 6H), 1.23–1.12 (m, 2H), 0.71 (d, J = 7.2 Hz, 3H). Synthesis 17: Synthesis of N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-N'-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-

fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3- piperidyl]methyl]decanediamide (Compound 17): To a stirred solution of 4-[4-[3-(aminomethyl)-1-piperidyl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoro-naphthalen-2-ol (A-2) (50 mg, 82.42 μmol) and 10-(((1-(2,6-dioxopiperidin-3-yl)-2-oxo- 1,2-dihydrobenzo[cd]indol-6-yl)methyl)amino)-10-oxodecanoic acid (C-15) (40.68 mg, 82.42 μmol) in N,N-dimethylformamide (1 mL) at 0 °C was added HATU (62.67 mg, 164.83 μmol)) followed by DIPEA (31.95 mg, 247.25 μmol, 43.07 μL). Then the reaction mixture was stirred at 25 °C for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford crude product (100 mg). The crude was purified by prep-HPLC to obtain N- [[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]-N'-[[1-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-piperidyl]methyl]decanediamide (Compound 17) (10 mg, 8.54 μmol, 10.36% yield, 92.37% purity) as white solid. Prep. HPLC condition: Column: X-BRIDGE C-18; Mobile Phase A: 5 mM ammonium bicarbonate in water; B: 100% ACN; Gradient (T%B): 0/30,2/30,12/60,13/60,13.1/100,17./100,17.1/30; Flow Rate: 18 mL/min; Sample Diluent: ACN+Water; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1082.67 [M-H]⁺; Retention time (min): 1.62; ¹H NMR (400 MHz, DMSO-d6): δ 11.11 (bs, 1H), 8.98 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 6.8 Hz, 1H), 7.94 (t, J = 7.6 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.70 (bs, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.37–7.28 (m, 2H), 7.06 (d, J = 7.2 Hz, 1H), 6.99 (s, 1H), 5.44–5.18 (m, 2H), 4.69 (d, J = 6.8 Hz, 1H), 4.52–4.37 (q, J = 8.8, 4.4 Hz, 2H), 4.13 (d, J = 7.2 Hz, 1H), 4.03 (d, J = 7.2 Hz, 1H), 3.44 (bs, 1H), 3.14–2.90 (m, 6H), 2.88–2.52 (m, 4H), 2.33 (s, 1H), 2.16–1.94 (m, 10H), 1.92–1.65 (m, 6H), 1.51–1.37 (bs, 7H), 1.18–1.03 (bs, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 18: Synthesis of N1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2- dihydrobenzo[cd]indol-6-yl)methyl)-N12-((1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methyl)dodecanediamide (Compound 18):

O NH NH N O H N O F N O 9 Et O N N N O N F OH F Compound 18 To a stirred solution of 12-(((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2- dihydrobenzo[cd]indol-6-yl)methyl)amino)-12-oxododecanoic acid (C-16) (78.24 mg, 150.00 μmol) and 4-(4-(3-(aminomethyl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (A-2) (70 mg, 115.38 μmol, 061) in N,N-dimethylformamide (1 mL) was added DIPEA (44.74 mg, 346.15 μmmol, 60.29 μL) followed by the addition of HATU (87.74 mg, 230.76 μmol) at room temperature. The reaction mixture was stirred at room temperature for two hours. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford crude product (90 mg). The resulting crude was purified by prep- HPLC to afford N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]-N'-[[1-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2S,8R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3- piperidyl]methyl]dodecanediamide (Compound 18) (13 mg, 10.88 μmol, 9.43% yield, 96.74% purity, formic acid) as white solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18; Mobile phase A: 5 mM ammonium bicarbonate in water; Mobile phase B: 100% ACN (Org); Gradient (Time/%B): 0/30, 2/30, 8/50, 16.5/50, 16.51/100, 19.0/100, 19.51/30, 22/30; Flow rate: 18 mL/min; Solubility: Acetonitrile+THF+Water; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1110.72 [M+H]⁺; Retention time (min): 1.70; ¹H NMR (400 MHz, DMSO-d6): δ 11.26 (bs, 1H), 10.08 (bs, 1H), 8.98 (d, J = 2.4 Hz, 1H), 8.35–8.31 (m, 2H), 8.09 (d, J = 6.8 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.75–7.71 (m, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.34–7.30 (m, 2H), 7.07 (d, J = 7.6 Hz, 1H), 7.01 (s, 1H), 5.48 (d, J = 7.6 Hz, 1H), 5.36–5.21 (m, 1H), 4.68 (d, J = 6.4 Hz, 2H), 4.50–4.37 (m, 2H), 4.14 (d, J = 7.6 Hz, 1H), 4.05 (d, J = 7.6 Hz, 1H), 3.20–2.91 (m, 8H), 2.88–2.52 (m, 3H), 2.34 (s, 1H), 2.19–1.97 (bs, 9H), 1.91–1.58 (m, 7H), 1.52–1.35 (m, 5H), 1.23–0.99 (m, 12H), 0.71 (t, J = 3.6 Hz, 3H). Synthesis 19: Synthesis of 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)- N-(3-((1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- hydroxypiperidin-3-yl)oxy)propyl)acetamide (Compound 19): To a stirred solution of 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)acetic acid (C-17) (27.44 mg, 59.73 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) was added DIPEA (27.57 mg, 213.31 μmol, 37.16 μL) and HATU (48.66 mg, 127.99 μmol) at 0 °C. The reaction mixture was stirred at same temperature for 5 minutes followed by addition of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]piperidin-3-ol (A-3) (60 mg, 85.33 μmol, hydrochloric acid). The reaction mixture was stirred at room temperature for 16 hours. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice-cold water (5 mL) and diluted with acetonitrile (1 mL). The reaction mixture was lyophilized to obtain crude compound, which was purified by prep-HPLC to afford 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-N-(3-((1- (7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-hydroxypiperidin-3- yl)oxy)propyl)acetamide (Compound 19) (13 mg, 12.33 μmol, 14.45% yield, 98.68% purity, Formic acid) as an off-white solid. Prep. HPLC condition: Column Name: C18; 250x20 mm;5μ; Column No#: GVKBLR/PREP/033; Mobile Phase-A: 0.10 % formic acid in water; Mobile Phase-B: acetonitrile; Flow Rate (mL/minute) :18; Sample Loading (mg/Injection): 6; No. of Injection's :10; Spot visualization: UV active compound; LCMS [ES⁺]: 994.62 [M+H]⁺; Retention time (min): 5.45; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 9.23 (d, J = 8.8 Hz, 1H), 7.77–7.73 (m, 1H), 7.68–7.62 (m, 1H), 7.36–7.32 (m, 2H), 7.04–7.01 (m, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 5.67 (d, J = 7.2 Hz, 1H), 5.36–5.21 (m, 2H), 4.33–3.94 (m, 7H), 3.89–3.48 (bs, 4H), 3.15–2.98 (m, 5H), 2.86–2.54 (m, 6H), 2.37–2.22 (m, 3H), 2.19– 1.88 (m, 8H), 1.85–1.69 (m, 6H), 1.66–1.49 (m, 6H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 20: Synthesis of 4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)- N-(3-((1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- hydroxypiperidin-3-yl)oxy)propyl)-4-oxobutanamide (Compound 20):

To a stirred solution of 3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1- yl)propanoic acid (C-1) (23.14 mg, 46.15 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) was added DIPEA (27.57 mg, 213.31 μmol, 37.16 μL) and HATU (48.66 mg, 127.99 μmol) at 0 °C. The reaction mixture was stirred at same temperature for 5 minutes followed by addition of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]piperidin-3-ol (A-3) (60 mg, 85.33 μmol, hydrochloric acid). The reaction mixture was stirred at room temperature for 16 hours. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice-cold water (5 mL) and diluted with acetonitrile (1 mL). The reaction mixture was lyophilized to obtain crude compound, which was purified by prep-HPLC to afford 4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-N-(3-((1- (7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-hydroxypiperidin-3- yl)oxy)propyl)-4-oxobutanamide (Compound 20) (24 mg, 21.09 μmol, 24.72% yield, 95.11% purity, formic acid) as an off-white solid. Prep. HPLC condition: Column Name: C18; 250x20 mm; 5μ; Column No#: GVKBLR/PREP/033; Mobile Phase-A: 0.10 % formic acid in water; Mobile Phase-B: acetonitrile; Flow Rate (mL/minute):18; Gradient program (T/%B): 0/15, 2/15, 10/38, 13.12/38, 13.13/100, 15/100, 15.01/15, 18/15; Sample Loading (mg/Injection): 6; No. of Injection's :10; Spot visualization: UV active compound; LCMS [ES⁺]: 1036.6 [M+H]⁺; Retention time (min): 1.47; ¹H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 10.27 (bs, 1H), 9.24 (d, J = 12.0 Hz, 1H), 7.77–7.72 (m, 2H), 7.36–7.32 (m, 2H), 7.05–7.02 (m, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 5.67 (d, J = 7.2 Hz, 1H), 5.36–5.21 (m, 2H), 4,62 (d, J = 8.8 Hz, 1H), 4.33–3.74 (m, 10H), 3.57–3.44 (bs, 4H), 3.15–2.89 (m, 6H), 2.84–2.54 (m, 3H), 2.37–2.22 (m, 3H), 2.19–1.88 (m, 6H), 1.85–1.63 (m, 8H), 1.61–1.38 (m, 4H), 1.33 (bs, 1H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 21: Synthesis of 7-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-N- [3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-hydroxy-3- piperidyl]oxy]propyl]-7-oxo-heptanamide (Compound 21): To a stirred solution of 7-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-7- oxo-heptanoic acid (C-2) (29.93 mg, 55.06 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) was added DIPEA (32.16 mg, 248.87 μmol, 43.35 μL) and HATU (56.78 mg, 149.32 μmol) at 0 °C. The reaction mixture was stirred at same temperature for 5 minutes followed by addition of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (A-3) (0.070 g, 99.55 μmol, hydrochloric acid). The reaction mixture was stirred at room temperature for 16 hours. The progress of reaction was monitored by TLC and LCMS. Reaction mixture was quenched with ice-cold water (5 mL) to afford precipitate. The obtained precipitate was filtered and dried to obtain crude which was purified by prep-HPLC to afford 7-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-5-hydroxy-3-piperidyl]oxy]propyl]-7-oxo-heptanamide (Compound 21) (23 mg, 20.27 μmol, 20.36% yield, 95.03% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-SELECT C-18; Mobile phase A: 5 mM ammonium acetate in water; Mobile phase B: ACN; Gradient (Time/%B): 0/20, 2/20, 8/45, 14/45, 14.1/100, 17/100, 17.1/20, 20/20; Flow rate: 18 mL/min; Solubility: H₂O+ACN; Spot visualization: UV active compound; LCMS [ES⁺]: 1078.76 [M+H]⁺; Retention time (min): 1.62; ¹H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 9.23 (d, J = 11.2 Hz, 1H), 7.77–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.72–7.65 (m, 1H), 7.36–7.32 (m, 2H), 7.03 (dd, J = 7.2, 3.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 5.65 (d, J = 7.2 Hz, 1H), 5.36–5.10 (m, 2H), 4.52 (d, J = 6.8 Hz, 1H), 4.28–3.76 (m, 9H), 3.52 (bs, 2H), 3.12–2.90 (m, 7H), 2.88–2.54 (m, 4H), 2.36–2.27 (m, 2H), 2.18–1.92 (m, 8H), 1.79–1.63 (m, 9H), 1.56–1.37 (m, 7H), 1.28–1.18 (m, 4H), 0.71 (t, J = 6.8 Hz, 3H). Synthesis 22: Synthesis of 10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-N- [3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-hydroxy-3- piperidyl]oxy]propyl]-10-oxo-decanamide (Compound 22):

To a stirred solution of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (A-3) (0.060 g, 85.33 μmol, hydrochloric acid) and 10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-10-oxo- decanoic acid (C-3) (34.98 mg, 59.73 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added HATU (48.66 mg, 127.99 μmol) followed by DIPEA (27.57 mg, 213.31 μmol, 37.16 μL). Then reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was monitored by TLC and LCMS. To the crude water was added water (5mL) to afford a solid. A solid was filtered to afford crude product. The crude was purified by Prep- HPLC to obtain the product 10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-N-[3- [[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-hydroxy-3- piperidyl]oxy]propyl]-10-oxo-decanamide (Compound 22) (19 mg, 16.65 μmol, 19.52% yield, 98.20% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-SELECT- C18; Mobile phase A: 0.1% FA in water; Mobile phase B: ACN; Gradient (Time/%B): 0/30, 2/30, 9/41, 13/41, 15/100, 15/100, 15.1/30, 18/30; Flow rate: 18 mL/min; Solubility: H₂O+ACN+THF; Spot visualization: UV active compound; LCMS [ES⁺]: 1120.72 [M+H]⁺; Retention time (min): 1.63; ¹H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 9.23 (d, J = 10.8 Hz, 1H), 7.77–7.64 (m, 2H), 7.36–7.32 (m, 2H), 7.05–7.02 (m, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 5.67 (d, J = 7.2 Hz, 1H), 5.36–5.21 (m, 2H), 4.52 (d, J = 8.8 Hz, 1H), 4.33–3.74 (m, 10H), 3.57–3.48 (bs, 3H), 3.15–2.89 (m, 6H), 2.84–2.54 (m, 3H), 2.37–2.22 (m, 3H), 2.19–1.88 (m, 8H), 1.85–1.63 (m, 9H), 1.61–1.38 (m, 8H), 1.23 (bs, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 23: Synthesis of 12-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-N- [3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-

1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-hydroxy-3- piperidyl]oxy]propyl]-12-oxo-dodecanamide (Compound 23): H O HO * * O N 9 N H O O N O F N Et N N N H N O N F OH F Compound 23 To a stirred solution of 12-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-12- oxo-dodecanoic acid (C-4) (36.65 mg, 59.73 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) was added DIPEA (33.08 mg, 255.98 μmol, 44.59 μL) and HATU (48.66 mg, 127.99 μmol) at 0 °C. The reaction mixture was stirred at same temperature for 5 minutes followed by addition of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (A-3) (60 mg, 85.33 μmol, hydrochloric acid). Reaction mixture was stirred at room temperature for 3 hours. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice-cold water (5 mL) and diluted with acetonitrile (1 mL). Reaction mixture was lyophilized to obtain crude compound, which was purified by prep-HPLC to afford 12-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-5-hydroxy-3-piperidyl]oxy]propyl]-12-oxo-dodecanamide (Compound 23) (36 mg, 30.72 μmol, 36.00% yield, 97.99% purity) as an off-white solid. Prep. HPLC condition: Column/ dimensions: KINETICS-C18- (21.5*250*5μm); Mobile phase A: 10 mM ammonium acetate in water; M bil h B i il G di (Ti /%B) 0/25, 1/25, 8/70, 13/70, 12.01/100, 22/100, 22.01/25, 24/25; Flow rate: 17 mL/min; Solubility: THF+ACN+Water; Spot visualization: UV active compound; LCMS [ES⁺]: 1148.77 [M+H]⁺; Retention time (min): 1.72; ¹H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 9.23 (d, J = 11.6 Hz, 1H), 7.77–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.72–7.64 (m, 1H), 7.36–7.32 (m, 2H), 7.03 (q, J = 7.2, 3.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 5.65 (d, J = 7.2 Hz, 1H), 5.36–5.10 (m, 2H), 4.52 (d, J = 6.8 Hz, 1H), 4.28 (t, J = 5.6 Hz, 1H), 4.15 (d, J = 7.8 Hz, 1H), 4.07 (d, J = 7.8 Hz, 1H), 4.03– 3.56 (m, 9H), 3.12–2.90 (m, 6H), 2.88–2.54 (m, 4H), 2.36–2.27 (m, 3H), 2.18–1.92 (m, 8H), 1.79–1.63 (m, 10H), 1.56–1.37 (m, 8H), 1.32–1.17 (m, 11H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 24: Synthesis of 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5- hydroxy-3-piperidyl]oxy]propyl]acetamide (Compound 24): To a stirred solution of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (A-3) (0.065 g, 92.44 μmol, hydrochloric acid) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]acetic acid (C-21) (33.29 mg, 64.70 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added HATU (35.15 mg, 92.44 μmol) followed by DIPEA (11.95 mg, 92.44 μmol, 16.10 μL). Then the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was monitored by TLC and LCMS. Then water (5 mL) was added to the reaction mixture to afford a solid, which was filtered to afford crude product. The crude was purified by Prep-HPLC to obtain the product 2-[4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-hydroxy-3-piperidyl]oxy]propyl]acetamide (Compound 24) (17 mg, 15.41 μmol, 16.68% yield, 95.13% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X –bridge C18 (19*250*5μ); Mobile phase A: 10 mM Ammonium acetate in water (aq); Mobile phase: acetonitrile; Gradient (Time/%B): 0/15, 2/15, 8/40, 13/40, 12.01/100; Flow rate: 17 mL/min; Solubility: Water+ACN+THF; Spot visualization: UV active compound; LCMS [ES⁺]: 1049.64 [M+H]⁺; Retention time (min): 1.23; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (bs, 1H), 9.23 (d, J = 11.2 Hz, 1H), 7.77–7.63 (m, 2H), 7.35–7.29 (m, 2H), 7.09–6.98 (m, 3H), 6.89 (d, J = 8.4 Hz, 1H), 5.36–5.21 (m, 2H), 4.29–3.98 (m, 6H), 3.91–3.56 (m, 5H), 3.34 (bs, 3H), 3.12–2.98 (m, 6H), 2.92–2.79 (m, 7H), 2.73–2.57 (m, 3H), 2.32 (s, 1H), 2.19–1.88 (m, 9H), 1.85–1.66 (m, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 25: Synthesis of 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5- hydroxy-3-piperidyl]oxy]propyl]-4-oxo-butanamide (Compound 25):

To a stirred solution of 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]-4-oxo-butanoic acid (C-5) (30.83 mg, 55.40 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) was added DIPEA (32.16 mg, 248.87 μmol, 43.35 μL) and HATU (56.78 mg, 149.32 μmol) at 0 °C. The reaction mixture was stirred at same temperature for 5 minutes followed by addition of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (A-3) (70 mg, 99.55 μmol, hydrochloric acid). The reaction mixture was stirred at room temperature for 16 hours. The progress of reaction was monitored by TLC and LCMS. Reaction mixture was quenched with ice-cold water (5 mL) to afford precipitate. The obtained precipitate was filtered and dried to obtain crude which was purified by prep-HPLC to afford 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-5-hydroxy-3-piperidyl]oxy]propyl]-4-oxo-butanamide (Compound 25) (23 mg, 20.11 μmol, 20.20% yield, 95.39% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18; Mobile phase A: 5 mM Ammonium acetate in water; Mobile phase B: ACN; Gradient (Time/%B): 0/20, 2/20, 10/45, 15/45, 15.01/100, 18.0/100, 18.1/20, 21/20; Flow rate: 18 mL/min; Solubility: H₂O+ACN; LCMS [ES⁺]: 1091.70 [M+H]⁺; Retention time (min): 4.53; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (bs, 1H), 9.23 (d, J = 12.4 Hz, 1H), 7.77–7.73 (q, J = 8.4, 5.6 Hz, 1H), 7.36–7.32 (m, 2H), 7.08 (s, 1H), 7.04–7.01 (m, 2H), 6.89 (d, J = 8.0 Hz, 2H), 5.37–5.12 (m, 3H), 4.54 (d, J = 6.8 Hz, 1H), 4.28–3.63 (m, 9H), 3.44 (bs, 4H), 3.12–2.90 (m, 9H), 2.88–2.54 (m, 4H), 2.34–2.29 (m, 2H), 2.18-1.92 (m, 6H), 1.86–1.71 (m, 10H), 1.66 1.38 (m, 4H), 0.71 (t, J = 6.8 Hz, 3H). Synthesis 26: Synthesis of 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5- hydroxy-3-piperidyl]oxy]propyl]-6-oxo-hexanamide (Compound 26): To a stirred solution of 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]-6-oxo-hexanoic acid (C-6) (29.64 mg, 62.99 μmol) in N,N-dimethylformamide (1.5 mL) was added DIPEA (29.08 mg, 224.98 μmol, 39.19 μL) and HATU (51.33 mg, 134.99 μmol) at 0 °C. The reaction mixture was stirred at same temperature for 5 minutes followed by addition of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]piperidin-3-ol (A-3) (60 mg, 89.99 μmol, hydrochloric acid). The reaction mixture was stirred at room temperature for 16 hours. The progress of reaction was monitored by TLC and LCMS. Reaction mixture was quenched with ice-cold water (5 mL) to afford precipitate. The obtained precipitate was filtered and dried to obtain crude which was purified by prep-HPLC to afford 6- [4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-[3-[[1-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-hydroxy-3- piperidyl]oxy]propyl]-6-oxo-hexanamide (Compound 26) (16 mg, 14.07 μmol, 15.63% yield, 98.42% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: C18; 250x20 mm; 5μ; Mobile h f i id i bil hase B: CAN; Gradient (Time/%B): 0/30, 2/30, 12/50, 13/50, 13.1/98, 16/98, 16.1/30, 19/30; Flow rate: 18 mL/min.; Solubility: H₂O+CAN; Spot visualization: UV active compound; LCMS [ES⁺]: 1119.69 [M+H]⁺; Retention time (min): 1.45; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (bs, 1H), 9.23 (d, J = 11.2 Hz, 1H), 7.77–7.70 (m, 2H), 7.36–7.32 (m, 2H), 7.09 (s, 1H), 7.04–7.01 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H), 5.36–5.21 (m, 3H), 4.54 (d, J = 6.8 Hz, 1H), 4.25–3.73 (m, 8H), 3.54 (bs, 3H), 3.15–2.54 (m, 13H), 2.36–2.27 (m, 2H), 2.18–1.92 (m, 8H), 1.89–1.68 (m, 5H), 1.65 (s, 5H), 1.56–1.37 (m, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 27: Synthesis of 10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin- 4-yl]-5-hydroxy-3-piperidyl]oxy]propyl]-10-oxo-decanamide (Compound 27): O H HO * * O N 7 N O F N O H N Et O N N N N N O N O F OH F Compound 27 To a stirred solution of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (A-3) (60 mg, 85.33 μmol, hydrochloric acid) in N,N-dimethylformamide (1 mL) was added 10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl- 2-oxo-benzimidazol-5-yl]-1-piperidyl]-10-oxo-decanoic acid (C-7) (38.26 mg, 59.73 μmol, trifluoroacetic acid) DIPEA (3308 25598 l 4459 L) d HATU (48.66 mg, 127.99 μmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice- cold water (5 mL) and diluted with acetonitrile (1 mL). Reaction mixture was lyophilized to obtain crude compound, which was purified by prep-HPLC to afford 10-[4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-hydroxy-3-piperidyl]oxy]propyl]-10-oxo- decanamide (Compound 27) (22 mg, 18.68 μmol, 21.89% yield, 99.80% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-SELECT CSH(10*150*5μm); Mobile phase A: 10 mM Ammonium acetate in water; Mobile phase B: acetonitrile; Gradient (Time/%B): 0/10, 1/10, 8/40, 16.65/40, 16.70/98, 20/98, 20.05/10, 22/10; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: 1175.76 [M+H]⁺; Retention time (min): 1.58; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (bs, 1H), 9.23 (d, J = 11.2 Hz, 1H), 7.77–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.72–7.64 (m, 1H), 7.36–7.32 (m, 2H), 7.08 (s, 1H), 7.04–7.01 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H), 5.36–5.21 (m, 3H), 4.54 (d, J = 6.8 Hz, 1H), 4.25–3.73 (m, 8H), 3.54 (bs, 5H), 3.15–2.54 (m, 13H), 2.36–2.27 (m, 3H), 2.18– 1.92 (m, 8H), 1.89–1.68 (m, 7H), 1.56–1.37 (m, 8H), 1.32–1.17 (m, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 28: Synthesis of 12-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin- 4-yl]-5-hydroxy-3-piperidyl]oxy]propyl]-12-oxo-dodecanamide (Compound 28):

To a stirred solution of 12-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-1-piperidyl]-12-oxo-dodecanoic acid (C-8) (33.28 mg, 49.77 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) was added DIPEA (27.57 mg, 213.31 μmol, 37.16 μL) and HATU (40.55 mg, 106.66 μmol) at 0 °C. The reaction mixture was stirred at same temperature for 5 minutes followed by the addition of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (A-3) (50 mg, 71.10 μmol, hydrochloric acid). Reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with ice-cold water (5 mL) and diluted with acetonitrile (1mL). The reaction mixture was lyophilized to obtain crude compound, which was purified by prep-HPLC to afford 12-[4-[1-(2,6-dioxo-3-piperidyl)-3- methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-hydroxy-3-piperidyl]oxy]propyl]-12-oxo- dodecanamide (Compound 28) (9 mg, 6.98 μmol, 9.81% yield, 93.28% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X BRIDGE PHENYL; Mobile phase A: 5 mM Ammonium acetate in water; Mobile phase B: Acetonitrile Gradient; Gradient (Time/%B): 0/20, 2/20, 14/55, 20/55, 20.1/100, 23.0/100; Flow rate: 18 mL/min; Solubility: ACN+Water; Spot visualization: UV active compound; LCMS [ES⁺]: 1203.83 [M+H]⁺; Retention time (min): 5.10; ¹H NMR (400 MHz, DMSO-d6): δ 11.20–10.55 (bs, 2H), 9.23 (d, J = 10.8 Hz, 1H), 7.77– 7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.72–7.64 (m, 1H), 7.35–7.31 (m, 2H), 7.08 (s, 1H), 7.04–7.01 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H), 5.36–5.21 (m, 2H), 4.54 (d, J = 6.8 Hz, 1H), 4.25–3.73 (m, 9H), 3.54 (bs, 5H), 3.15–2.54 (m, 13H), 2.36–2.27 (m, 2H), 2.18–1.92 (m, 8H), 1.89–1.68 (m, 5H), 1.56–1.37 (m, 8H), 1.32–1.17 (m, 14H), 0.71 (t, J = 6.8 Hz, 3H). Synthesis 29: Synthesis of 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5- hydroxy-3-piperidyl]oxy]propyl]-4-oxo-butanamide (Compound 29): To a stirred solution of 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-1-piperidyl]-4-oxo-butanoic acid (C-9) (30.83 mg, 55.40 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) was added DIPEA (32.16 mg, 248.87 μmol, 43.35 μL) and HATU (56.78 mg, 149.32 μmol) at 0 ℃. The reaction mixture was stirred at same temperature for 5 minutes followed by addition of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (A-3) (70 mg, 99.55 μmol, hydrochloric acid). The reaction mixture was stirred at room temperature for 16 hours. The progress of reaction was monitored by TLC and LCMS. Reaction mixture was quenched with ice-cold water (5 mL) to afford precipitate. The obtained precipitate was filtered and dried to obtain crude which was purified by prep-HPLC to afford 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-4-yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-5-hydroxy-3-piperidyl]oxy]propyl]-4-oxo-butanamide (Compound 29) (17 mg, 14.85 μmol, 14.92% yield, 95.33% purity)) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18; Mobile phase A: 5 mM Ammonium acetate in water; Mobile phase B: ACN; Gradient (Time/%B): 0/20, 2/20, 8/45, 14/45, 14.1/100, 17/100, 17.1/20, 20/20; Flow rate: 18 mL/min; Solubility: H2O+CAN; Spot visualization: UV active compound; LCMS [ES⁺]: 1091.62 [M+H]⁺; Retention time (min): 4.51; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (bs, 1H), 9.23 (d, J = 11.2 Hz, 1H), 7.79–7.72 (q, J = 8.8, 6.0 Hz, 1H), 7.35–7.31 (m, 2H), 7.06–6.96 (m, 4H), 5.39–5.19 (m, 2H), 4.54 (d, J = 6.8 Hz, 1H), 4.23–3.73 (m, 8H), 3.63 (s, 3H), 3.59–3.55 (bs, 3H), 3.15–2.54 (m, 12H), 2.36–2.27 (m, 2H), 2.18–1.93 (m, 6H), 1.89–1.72 (m, 8H), 1.56–1.47 (m, 8H), 0.71 (t, J = 6.8 Hz, 3H). Synthesis 30: Synthesis of 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5- hydroxy-3-piperidyl]oxy]propyl]-6-oxo-hexanamide (Compound 30): To a stirred solution of 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-1-piperidyl]-6-oxo-hexanoic acid (C-10) (54.03 mg, 92.44 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) was added DIPEA (29.87 mg, 231.09 μmol, 40.25 μL) and HATU (52.72 mg, 138.65 μmol) at 0 °C. The reaction mixture was stirred at same temperature for 5 minutes followed by addition of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro 2 [[(2R 8S) 2 fl 123567 h h d li in-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (A-3) (65 mg, 92.44 μmol, hydrochloric acid). The reaction mixture was stirred at room temperature for 16 hours. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (5 mL) and acetonitrile (0.5 mL). The reaction mixture was lyophilized to afford crude mass. The obtained crude mass was purified by prep-HPLC to afford 6-[4-[1-(2,6-dioxo-3-piperidyl)-3- methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-hydroxy-3-piperidyl]oxy]propyl]-6-oxo- hexanamide (Compound 30) (24 mg, 19.15 μmol, 20.72% yield, 93% purity, formic acid) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18; 150x20 mm; 5μ; Mobile phase A: 0.10 % Formic acid in water; Mobile phase B: ACN; Gradient (Time/%B): 0/15, 2/15, 10/45, 25/45, 25.1/100, 28/100, 28.1/10, 31/10; Flow rate: 18 mL/min; Solubility: H2O+ACN; Spot visualization: UV active compound; LCMS [ES⁺]: 1119.69 [M+H]⁺; Retention time (min): 1.43; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (bs, 1H), 9.23 (d, J = 12.4 Hz, 1H), 7.78–7.68 (m, 2H), 7.36–7.32 (m, 2H), 7.05–6.96 (m, 4H), 5.39–5.19 (m, 2H), 4.55 (d, J = 6.8 Hz, 1H), 4.26–3.79 (m, 8H), 3.75 (bs, 2H), 3.61 (s, 3H), 3.48 (bs, 4H), 3.18–2.77 (m, 8H), 2.71– 2.57 (m, 3H), 2.32 (s, 3H), 2.21–1.93 (m, 8H), 1.91–1.70 (m, 6H), 1.63–1.40 (bs, 8H), 0.71 (t, J = 6.8 Hz, 3H). Synthesis 31: Synthesis of 10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 4-yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin- 4-yl]-5-hydroxy-3-piperidyl]oxy]propyl]-10-oxo-decanamide (Compound 31):

To a stirred solution of 10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 4-yl]-1-piperidyl]-10-oxo-decanoic acid (C-11) (38.26 mg, 59.73 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.0 mL) was added DIPEA (33.08 mg, 255.98 μmol, 44.59 μL) and HATU (48.66 mg, 127.99 μmol) at 0 °C. The reaction mixture was stirred at same temperature for 5 minutes followed by addition of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (A-3) (60 mg, 85.33 μmol, hydrochloric acid). Reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with ice-cold water (5 mL) and diluted with acetonitrile (1 mL). Reaction mixture was lyophilized to obtain crude compound, which was purified by prep-HPLC to afford 10-[4-[1-(2,6-dioxo-3-piperidyl)-3- methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-hydroxy-3-piperidyl]oxy]propyl]-10-oxo- decanamide (Compound 31) (23 mg, 19.22 μmol, 22.53% yield, 98.22% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-SELECT CSH (10*150*5μm); Mobile phase A: 10 mM Ammonium acetate in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/10, 1/10, 8/40, 16.5/40, 16.6/100, 20/100, 20.1/10, 22/10; Flow rate: 17 mL/min; Solubility: Acetonitrile+Water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: 1175.76 [M+H]⁺; Retention time (min): 1.58; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (bs, 1H), 9.23 (d, J = 11.2 Hz, 1H), 7.77–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.72–7.64 (m, 1H), 7.36–7.32 (m, 2H), 7.04–6.96 (m, 4H), 5.36–5.16 (m, 3H), 4.54 (d, J = 6.8 Hz, 1H), 4.25–3.73 (m, 8H), 3.63 (s, 3H), 3.59–3.55 (bs, 5H), 3.15–2.54 (m, 11H), 2.36–2.27 (m, 2H), 2.18–1.92 (m, 8H), 1.89– 1.68 (m, 7H), 1.56–1.37 (m, 8H), 1.32–1.17 (m, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 32: Synthesis of 12-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5- hydroxy-3-piperidyl]oxy]propyl]-12-oxo-dodecanamide (Compound 32): To a stirred solution of 12-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 4-yl]-1-piperidyl]-12-oxo-dodecanoic acid (C-12) (39.94 mg, 59.73 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) was added DIPEA (33.08 mg, 255.98 μmol, 44.59 μL) and HATU (48.66 mg, 127.99 μmol) at 0 °C. The reaction mixture was stirred at same temperature for 5 minutes followed by addition of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (A-3) (60 mg, 85.33 μmol, hydrochloric acid). Reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with ice-cold water (5 mL) and diluted with acetonitrile (1 mL). Reaction mixture was lyophilized to obtain crude compound, which was purified by prep-HPLC to afford 12-[4-[1-(2,6-dioxo-3-piperidyl)-3- methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[43-d]pyrimidin-4-yl]-5-hydroxy-3-piperidyl]oxy]propyl]-12-oxo- dodecanamide (Compound 32) (33 mg, 27.32 μmol, 32.01% yield, 99.61% purity) as an off- white solid. Prep. HPLC condition: Column/dimensions: KINETICS-C18-(21.5*250*5μm); Mobile phase A: 10 mM Ammonium acetate in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/20, 1/20, 8/62, 13/62, 13.01/100, 20/100, 20.01/20, 22/20; Flow rate: 17 mL/min; Solubility: THF+ACN +Water; Spot visualization: UV active compound; LCMS [ES⁺]: 1203.81 [M+H]⁺; Retention time (min): 1.67; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (bs, 1H), 9.23 (d, J = 12.0 Hz, 1H), 7.77–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.72–7.64 (m, 1H), 7.36–7.32 (m, 2H), 7.04–6.94 (m, 4H), 5.36–5.16 (m, 3H), 4.56 (d, J = 6.8 Hz, 1H), 4.25–3.73 (m, 9H), 3.63 (s, 3H), 3.59–3.55 (bs, 4H), 3.15–2.54 (m, 12H), 2.36–2.27 (m, 2H), 2.18–1.92 (m, 7H), 1.89–1.68 (m, 6H), 1.56–1.37 (m, 9H), 1.32–1.17 (m, 12H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 33: Synthesis of N'-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-N-[3-[[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5- hydroxy-3-piperidyl]oxy]propyl]dodecanediamide (Compound 33): To a stirred solution of 12-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methylamino]-1 ol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) was added DIPEA (23.89 mg, 184.87 μmol, 32.20 μL) and HATU (52.72 mg, 138.65 μmol) at 0 °C. The reaction mixture was stirred at same temperature for 5 minutes followed by addition of 5-(3-aminopropoxy)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (A-3) (65 mg, 92.44 μmol, hydrochloric acid). The reaction mixture was stirred at room temperature for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with ice-cold water (5 mL) and diluted with acetonitrile (0.5 mL). The reaction mixture was lyophilized to remove N,N-dimethylformamide. The obtained obtain crude was purified by prep-HPLC to afford N'-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]-N-[3- [[1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-hydroxy-3- piperidyl]oxy]propyl]dodecanediamide (Compound 33) (26 mg, 21.96 μmol, 23.76% yield, 98.85% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X- BRIDGEC18 19*250mm, 5μm; Mobile phase A: 5 mM ammonium acetate in water; Mobile phase B: ACN; Gradient (Time/%B): 00/202/208/4012/4013/10014/10015/40; Flow rate: 18 mL/min; Solubility: THF+H₂O+ACN; Spot visualization: UV active compound; LCMS [ES⁺]: 1170.74 [M+H]⁺; Retention time (min): 1.62; ¹H NMR (400 MHz, DMSO-d6): δ 11.1 (s, 1H), 9.98 (bs, 1H), 9.23 (d, J = 12.4 Hz, 1H), 8.35–8.27 (m, 2H), 8.10 (d, J = 6.8 Hz, 1H), 7.84 (t, J = 7.2 Hz, 1H), 7.78–7.71 (m, 1H), 7.69–7.61 (m, 1H), 7.41–7.29 (m, 3H), 7.08 (d, J = 6.8 Hz, 1H), 7.02 (d, J = 6.8 Hz, 1H), 5.38–5.09 (m, 3H), 4.67 (d, J = 7.2 Hz, 1H), 4.26–3.93 (m, 5H), 3.88–3.61 (m, 2H), 3.54–3.47 (m, 2H), 3.12–2.88 (m, 6H), 2.85–2.62 (m, 3H), 2.32 (bs, 1H), 2.18–2.01 (m, 7H), 1.97 (bs, 4H), 1.87–1.72 (m, 5H), 1.57–1.36 (m, 6H), 1.24–1.09 (bs, 12H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 34: Synthesis of 3-[4-[1-[2-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo- ethyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 34): To a stirred solution of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]acetic acid (C-17) (25.65 mg, 55.83 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (30.93 mg, 239.29 μmol, 41.68 μL) followed by HATU (45.49 mg, 119.64 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (60 mg, 79.76 μmol, hydrochloric acid) was added. Then the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by LCMS. After completion of starting material, the reaction mixture was quenched with ice-cold water (10 mL). Then filtered, the obtained solid was dried under reduced pressure to afford a crude product (53 mg). The crude product (53 mg) was purified by Prep-HPLC to afford 3-[4- [1-[2-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1- methyl-pyrazole-3 anilino]piperidine-2,6- dione (Compound 34) (6.1 mg, 5.60 μmol, 7.02% yield, 95.78% purity) as an off white solid. Prep. HPLC condition: Column: Acquity UPLC BEH C18, 1.7ìm (50 mm x 2.1 mm); Mobile Phase A: 0.1% Formic acid in qater; Mobile Phase B: 100% CAN; Gradient (T%B): 0/3, 1.0/3, 7.0/95, 7.5/95, 9.0/3, 10/3; Flow Rate: 0.5 mL/min; Sample Diluent: ACN+Water; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1043.67 [M+H]⁺; Retention time (min): 1.32; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (bs, 1H), 9.66 (bs, 1H), 9.35 (s, 1H), 7.77–7.73 (q, J = 9.2, 6.0 Hz, 1H), 7.36–7.31 (m, 2H), 7.00 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.64 (s, 1H), 6.59 (d, J = 8.8 Hz, 2H), 5.65 (d, J = 7.2 Hz, 1H), 5.36–5.21 (m, 1H), 4.85 (d, J = 7.2 Hz, 2H), 4.28 (t, J = 5.6 Hz, 1H), 4.15 (d, J = 7.8 Hz, 1H), 4.07 (d, J = 7.8 Hz, 1H), 4.03–3.88 (m, 6H), 3.68–3.42 (m, 6H), 3.18–2.98 (m, 5H), 2.93–2.54 (m, 7H), 2.38 (s, 1H), 2.17–1.96 (m, 6H), 1.57–1.41 (m, 8H), 0.70 (t, J = 7.6 Hz, 3H). Synthesis 35: Synthesis of 3-[4-[1-[2-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo- ethyl]-4-piperidyl]anilino]-1-methyl-piperidine-2,6-dione (Compound 35):

To a stirred solution 2-[4-[4-[(1-methyl-2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]acetic acid (C-17) (29.47 mg, 62.25 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (36.08 mg, 279.17 μmol, 48.63 μL) followed by HATU (53.07 mg, 139.59 μmol). After 5 minutes at room temperature, [5-[[[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazol-3-yl]-piperazin-1-yl-methanone (A-4) (70 mg, 93.06 μmol, hydrochloric acid) was added. The reaction mixture was stirred at 25 ℃ for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtain crude compound. The crude was purified by Prep-HPLC to afford 3-[4-[1-[2-[4-[5-[[[7-(8-ethyl- 7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]anilino]-1-methyl-piperidine- 2,6-dione (Compound 35) (11 mg, 10.01 μmol, 10.75% yield, 96.17% purity) as off-white solid. Prep-HPLC condition: Column/dimensions: X- SELECT C18 (250*19) 5μ. Mobile phase A: 10 mM Ammonium bicarbonate in water (aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/40, 3/40, 7/55, 14/55, 14.10/98/16/98, 16.1/30, 18/30; Flow rate: 17 mL/min; Solubility: Acetonitrile+THF+water; Spot visualization: UV active compound; LCMS [ES⁺]: 1057.59 [M+H]⁺; Retention time (min): 1.34; ¹H NMR (400 MHz, DMSO-d6): δ 10.06–9.12 (bs, 2H), 7.73–7.68 (m, 1H), 7.33–7.24 (m, 2H), 6.94 (d, J = 8.4 Hz, 3H), 6.59 (d, J = 8.0 Hz, 3H), 5.70 (d, J = 7.6 Hz, 1H), 5.35–5.22 (m, 1H), 4.78 (bs, 2H), 4.35 (bs, 1H), 4.14 (d, J = 8.8 Hz, 1H), 4.09–3.91 (m, 6H), 3.71–3.44 (bs, 6H), 3.18–2.89 (m, 8H), 2.88–2.69 (m, 6H), 2.34 (bs, 2H), 2.18–1.93 (m, 7H), 1.92–1.64 (m, 6H), 1.61–1.48 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 36: Synthesis of 3-[4-[1-[4-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-4-oxo- butanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 36): To a stirred solution of 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-4- oxo-butanoic acid (C-1) (28.00 mg, 55.83 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (30.93 mg, 239.29 μmol, 41.68 μL) followed by HATU (45.49 mg, 119.64 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1-yl-methanone (A-4) (60 mg, 79.76 μmol, hydrochloric acid) was added. Then the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by LCMS. After completion of starting material the reaction mixture was quenched with ice-cold water (10 mL) solid was obtained. Then filtered the solid and dried under reduced pressure to afford crude product (67 mg). The crude product (67mg) was purified by Prep-HPLC to afford 3-[4-[1-[4-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy- 1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3- carbonyl]piperazin-1-yl]-4-oxo-butanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 36) (13 mg, 11.05 μmol, 13.85% yield, 96.15% purity, Formic acid) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18 (19*150); Mobile phase A: 0.1% FA-in water (aq); Mobile phase B: ACN; Gradient (Time/%B): 0/20 2/20 12/60 13/60 14/100; Flow rate: 17 mL/min; Solubility: Acetonitrile+THF; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1085.70 [M+H]⁺; Retention time (min): 4.67; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (bs, 1H), 9.57 (bs, 1H), 9.35 (s, 1H), 7.77–7.73 (q, J = 9.2, 6.0 Hz, 1H), 7.36–7.31 (m, 2H), 7.00 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.64 (s, 1H), 6.59 (d, J = 8.8 Hz, 2H), 5.66 (d, J = 7.2 Hz, 1H), 5.36–5.21 (m, 1H), 4.85 (d, J = 7.2 Hz, 2H), 4.52 (d, J = 6.8 Hz, 1H), 4.28 (t, J = 5.6 Hz, 1H), 4.15 (d, J = 7.8 Hz, 1H), 4.07 (d, J = 7.8 Hz, 1H), 4.03–3.88 (m, 6H), 3.68–3.42 (m, 6H), 3.18–2.98 (m, 4H), 2.88–2.54 (m, 8H), 2.38 (s, 1H), 2.17–1.96 (m, 5H), 1.89–1.64 (m, 7H), 1.57–1.29 (m, 2H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 37: Synthesis of 3-[4-[1-[7-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-7-oxo- heptanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 37): O N _NH H N N HO N N O O _N H O F HN O C-2 N N HATU, DIPEA, DMF, RT, 16h N O N F OH F A-4

To a stirred solution of 7-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-7- oxo-heptanoic acid (C-2) (30.35 mg, 55.83 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (30.93 mg, 239.29 μmol, 41.68 μL) followed by HATU (45.49 mg, 119.64 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (60 mg, 79.76 μmol, hydrochloric acid) was added. Then reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by LCMS. After completion of starting material the reaction mixture was quenched with ice-cold water (10 mL) solid was obtained. Then filtered the solid and dried under reduced pressure to afford crude (53mg). The crude (53 mg) was purified by Prep-HPLC to afford 3-[4-[1-[7-[4-[5-[[[7-(8-ethyl- 7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazole-3-carbonyl]piperazin-1-yl]-7-oxo-heptanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 37) (21 mg, 18.03 μmol, 22.61% yield, 96.79% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: KINETEX C18 (19*250, 5μm); Mobile phase A: 5 mM Ammonium acetate in water (aq); Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/2, 2/2, 8/45, 16/45, 16.10/100; Flow rate: 18mL/min; Solubility: ACN +Water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1127.71 [M+H]⁺; Retention time (min): 1.52; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (bs, 1H), 9.66 (bs, 1H), 9.34 (s, 1H), 7.77–7.73 (q, J = 9.2, 6.0 Hz, 1H), 7.36–7.31 (m, 2H), 7.00 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.64 (s, 1H), 6.60 (d, J = 8.8 Hz, 2H), 5.65 (d, J = 7.2 Hz, 1H), 5.36–5.21 (m, 1H), 4.85 (d, J = 7.2 Hz, 2H), 4.52 (d, J = 6.8 Hz, 1H), 4.28 (t, J = 5.6 Hz, 1H), 4.15 (d, J = 7.8 Hz, 1H), 4.07 (d, J = 7.8 Hz, 1H), 4.03–3.88 (m, 7H), 3.68–3.42 (m, 7H), 3.13–2.98 (m, 4H), 2.83–2.54 (m, 5H), 2.38–2.28 (m, 4H), 2.17–1.96 (m, 6H), 1.57–1.41 (m, 5H), 1.39–1.28 (m, 5H), 1.32 (bs, 3H), 0.70 (t, J = 6.8 Hz, 3H). Synthesis 38: Synthesis of 3-[4-[1-[10-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-10-oxo- decanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 38): To a stirred solution of 10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-10- oxo-decanoic acid (C-3) (26.33 mg, 44.96 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (30.93 mg, 239.29 μmol, 41.68 μL) followed by HATU (45.49 mg, 119.64 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]- h l l l i i l h (A-4) (60 mg, 79.76 μmol, hydrochloric acid) was added. Then reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by LCMS. After completion of starting material, the reaction mixture was quenched with ice-cold water (10 mL) solid was obtained. Then filtered the solid and dried under reduced pressure to afford crude (67 mg). The crude (67 mg) was purified by Prep-HPLC to afford 3-[4-[1-[10-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3- carbonyl]piperazin-1-yl]-10-oxo-decanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 38) (25 mg, 20.55 μmol, 25.77% yield, 96.13% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-Bridge-C18; Mobile phase A: 5mM Ammonium acetate in water (aq); Mobile phase B: Acetonitrile; Gradient (Time/%B) 0/22, 2/22, 10/50, 25/50, 30/100; Flow rate: 17 mL/min; Solubility: ACN+THF+Water; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1169.82 [M+H]⁺; Retention time (min): 5.03; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (bs, 1H), 9.57 (bs, 1H), 9.35 (s, 1H), 7.77–7.73 (q, J = 9.2, 6.0 Hz, 1H), 7.36–7.31 (m, 2H), 7.00 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.64 (s, 1H), 6.59 (d, J = 8.8 Hz, 2H), 5.66 (d, J = 7.2 Hz, 1H), 5.36–5.21 (m, 1H), 4.85 (d, J = 7.2 Hz, 2H), 4.52 (d, J = 6.8 Hz, 1H), 4.28 (t, J = 5.6 Hz, 1H), 4.15 (d, J = 7.8 Hz, 1H), 4.07 (d, J = 7.8 Hz, 1H), 4.03–3.88 (m, 7H), 3.63–3.48 (m, 6H), 3.11–2.98 (m, 4H), 2.88–2.56 (m, 4H), 2.36 (bs, 4H), 2.17–1.94 (m, 5H), 1.89–1.68 (m, 9H), 1.48 (bs, 5H), 1.28 (bs, 8H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 39: Synthesis of 3-[4-[1-[12-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-12-oxo- dodecanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 39):

To a stirred solution of 12-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-12- oxo-dodecanoic acid (C-4) (39.97 mg, 65.14 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (36.08 mg, 279.17 μmol, 48.63 μL) followed by HATU (53.07 mg, 139.59 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (70 mg, 93.06 μmol, hydrochloric acid) was added. Then reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by LCMS. After completion of starting material the reaction mixture was quenched with ice-cold water (10 mL) solid was obtained. Then filtered the solid and dried under reduced pressure to afford crude. The crude was purified by Prep-HPLC to afford 3-[4-[1-[12-[4-[5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3- carbonyl]piperazin-1-yl]-12-oxo-dodecanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 39) (28 mg, 23.09 μmol, 24.81% yield, 98.74% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18; Mobile phase A: 5 mM ammonium bicarbonate in water; Mobile phase B: ACN; Gradient (Time/%B): 0/20, 2/20, 10/60, 25/60, 35/60, 35.1/100, 38/100, 38.1/20; Flow rate: 18 mL/min; Solubility: H2O+ACN; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1197.81 [M+H]⁺; Retention time (min): 1.73; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (bs, 1H), 9.66 (bs, 1H), 9.34 (s, 1H), 7.77–7.73 (q, J = 9.2, 6.0 Hz, 1H), 7.36–7.31 (m, 2H), 7.00 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 6.38 (m, 3H) , 5.66 (d, J = 7.2, 1H), 5.36–5.21 (m, 1H), 4.85 (d, J = 7.2 Hz, 2H), 4.52 (d, J = 6.8 Hz, 1H), 4.28 (t, J = 5.6 Hz, 1H), 4.15 (d, J = 7.8 Hz, 1H), 4.07 (d, J = 7.8 Hz, 1H), 4.03–3.88 (m, 6H), 3.68–3.42 (m, 6H), 3.11–2.98 (m, 4H), 2.83–2.54 (m, 4H), 2.38–2.23 (m, 5H), 2.17–1.96 (m, 5H), 1.77–1.59 (m, 9H), 1.56–1.40 (m, 5H), 1.35–1.21 (m, 10H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 40: Synthesis of 3-[5-[1-[2-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo- ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 40): To a stirred solution 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]acetic acid (C-21) (38.30 mg, 74.45 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (36.08 mg, 279.17 μmol, 48.63 μL) followed by HATU (53.07 mg, 139.59 μmol). After 5 minutes at room temperature, [5-[[[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazol-3-yl]-piperazin-1-yl-methanone (A-4) (70 mg, 93.06 μmol, hydrochloric acid) was added. The reaction mixture was stirred at 25 °C for 12 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtain crude compound. The crude was purified by Prep-HPLC to afford 3-[5-[1-[2-[4-[5-[[[7-(8-ethyl- 7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol- 1-yl]piperidine-2,6-dione (Compound 40) (27 mg, 24.10 μmol, 25.90% yield, 98.04% purity) as off-white solid. Prep-HPLC condition: Column/dimensions: X- SELECT C18 (250*19) 5μ; Mobile phase A: 10 mM Ammonium bicarbonate in water (aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/30,3/30,7/55,12/55,12.10/98/14/98,14.1/30,16/30; Flow rate: 17 mL/min; Solubility: Acetonitrile+THF+water; Spot visualization: UV active compound. LCMS [ES⁺]: 1098.45 [M+H]⁺; Retention time (min): 1.28; ¹H NMR (400 MHz, DMSO-d6): δ 11.12–10.46 (bs, 1H), 9.96–9.48 (bs, 1H), 9.27 (s, 1H), 7.77–7.73 (m, 1H), 7.38–7.28 (m, 2H), 7.08 (s, 1H), 7.00–6.89 (m, 3H), 6.63 (s, 1H), 5.47–5.21 (m, 2H), 4.92–4.78 (q, J = 10.6, 5.6 Hz, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09–4.04 (m, 2H), 4.02–3.82 (m, 4H), 3.71–3.48 (bs, 6H), 3.38 (bs, 3H), 3.26 (bs, 2H), 3.18–2.78 (m, 8H), 2.73–2.58 (m, 3H), 2.32 (bs, 1H), 2.18–1.92 (m, 6H), 1.88–1.62 (m, 8H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 41: Synthesis of 3-[5-[1-[4-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-4-oxo- butanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 41):

To a stirred solution of 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]-4-oxo-butanoic acid (C-5) (36.25 mg, 65.14 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) at 0 ℃ was added DIPEA (36.08 mg, 279.17 μmol, 48.63 μL) followed by HATU (56.61 mg, 148.89 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (70 mg, 93.06 μmol, hydrochloric acid) was added. Then reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of starting material the reaction mixture was quenched with ice-cold water (10 mL) solid was obtained. Then filtered the solid and dried under reduced pressure to afford Crude (65 mg). The crude (65 mg) was purified by Prep-HPLC to afford 3-[5-[1-[4-[4- [5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazole-3-carbonyl]piperazin-1-yl]-4-oxo-butanoyl]-4-piperidyl]-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (Compound 41) (16 mg, 13.34 μmol, 14.34% yield, 95.08% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18; Mobile phase A: 5 mM Ammonium bicarbonate in water; Mobile phase B: ACN; Gradient (Time/%B): 0/30, 2/30, 14/45, 14.1/100, 17/100, 17.1/30, 20/30; Flow rate: 18 mL/min; Solubility: H2O+CAN; LCMS [ES⁺]: m/z 1140.64 [M+H]⁺; Retention time (min): 1.46; Spot visualization: UV active compound; ¹H NMR (400 MHz, DMSO-d6): δ 10.26 (bs, 1H), 9.19 (s, 1H), 7.76–7.72 (m, 1H), 7.35–7.26 (m, 2H), 7.09 (s, 1H), 7.04–6.97 (bs, 3H), 6.60 (s, 1H), 5.38– 5.22 (m, 2H), 4.81 (q, J = 8.8, 4.4 Hz, 2H), 4.57 (d, J = 6.8 Hz, 1H), 4.15 (d, J = 7.2 Hz, 1H), 4.09–3.93 (m, 7H), 3.69–3.47 (m, 6H), 3.33 (bs, 3H), 3.16–2.91 (m, 5H), 2.80–2.68 (m, 4H), 2.64–2.50 (m, 5H), 2.32 (bs, 1H), 2.19–1.91 (m, 6H), 1.87–1.71 (m, 7H), 1.51 (bs, 1H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 42: Synthesis of 3-[5-[1-[6-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-6-oxo- hexanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 42): To a stirred solution of 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]-6-oxo-hexanoic acid (C-6) (38.08 mg, 65.14 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (36.08 mg, 279.17 μmol, 48.63 μL) followed by HATU (53.07 mg, 139.59 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (70 mg, 93.06 μmol, hydrochloric acid) was added. Then reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by LCMS. After completion of starting material the reaction mixture was quenched with ice-cold water (10 mL) solid was obtained. Then filtered the solid and dried under reduced pressure to afford crude product. The crude product was purified by Prep-HPLC to afford 3-[5-[1-[6-[4-[5-[[[7-(8-ethyl- 7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazole-3-carbonyl]piperazin-1-yl]-6-oxo-hexanoyl]-4-piperidyl]-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (Compound 42) (9 mg, 7.37 μmol, 7.92% yield, 95.67% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X BRIDGE- PHENYL( 19*250, 5μm); Mobile phase A: 10 mM Ammonium acetate in water; Mobile phase B: Acetonitrile (ORG); Gradient (Time/%B): 0/10, 1/10, 8/43, 18.5/43, 18.6/100, 25/100, 25.1/10, 27/10; Flow rate: 17 mL/min; Solubility: ACN+THF+Water; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1169.74 [M+H]⁺; Retention time (min): 4.58; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (bs, 1H), 9.76 (bs, 1H), 9.35 (s, 1H), 7.75–7.72 (q, J = 8.8 Hz, 6.0 Hz, 1H), 7.35–7.31 (m, 2H), 7.10 (s, 1H), 7.04–6.99 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 5.40–5.22 (m, 2H), 4.84 (d, J = 8.4 Hz, 2H), 4.57 (d, J = 7.6 Hz, 1H), 4.15 (d, J = 7.2 Hz, 1H), 4.08 (d, J = 7.2 Hz, 1H), 4.06–3.89 (m, 6H), 3.69–3.44 (bs, 7H), 3.29–2.99 (m, 4H), 2.87– 2.54 (m, 7H), 2.34 (bs, 4H), 2.18–1.93 (m, 4H), 1.86–1.72 (m, 5H), 1.65–1.52 (m, 10H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 43: Synthesis of 3-(5-(1-(10-(4-(5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-methyl-1H-pyrazole-3-

carbonyl)piperazin-1-yl)-10-oxodecanoyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound 43): To a stirred solution of [5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1-yl-methanone (A-4) (60 mg, 79.76 μmol, hydrochloric acid) and 10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]-10-oxo-decanoic acid (C-7) (33.22 mg, 51.85 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (30.93 mg, 239.29 μmol, 41.68 μL) followed by HATU (45.49 mg, 119.64 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was monitored by TLC and LCMS. The reaction progress was monitored by LCMS. After completion of starting material, the reaction mixture was quenched with ice-cold water (5 mL) solid was obtained. Then the solid was filtered and dried under reduced pressure to afford crude product. The crude product was purified by Prep-HPLC to afford 3-(5-(1-(10-(4-(5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)methyl)-1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)-10- oxodecanoyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione (Compound 43) (35 mg, 27.78 μmol, 34.82% yield, 97.17% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X BRIDGE; Mobile phase A: 10 mM Ammonium acetate in water; Mobile phase B: Acetonitrile (ORG); Gradient (Time/%B): 0/10, 2/10, 10/60, 12/60, 12.1/98, 15/98, 15.4/10, 18/10; Flow rate: 18 mL/min; Solubility: ACN+THF+water; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1224.75 [M+H]⁺; Retention time (min): 1.60; ¹H NMR (400 MHz, DMSO-d6): δ 11.10 (bs, 1H), 9.86 (bs, 1H), 9.36 (s, 1H), 7.77–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.10 (s, 1H), 7.02– 6.99 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 5.40–5.22 (m, 2H), 4.84 (d, J = 8.4 Hz, 2H), 4.57 (d, J = 7.6 Hz, 1H), 4.15 (d, J = 7.2 Hz, 1H), 4.08 (d, J = 7.2 Hz, 1H), 4.06–3.89 (m, 5H), 3.66–3.45 (m, 5H), 3.33 (bs, 3H), 3.12–2.98 (m, 4H), 2.92–2.56 (m, 5H), 2.34 (bs, 4H), 2.19– 1.96 (m, 5H), 1.90–1.70 (m, 9H), 1.58–1.37 (m, 7H), 1.28 (s, 8H), (t, J = 7.2 Hz, 3H). Synthesis 44: Synthesis of 3-[5-[1-[12-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-12-oxo- dodecanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 44):

To a stirred solution of 12-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-1-piperidyl]-12-oxo-dodecanoic acid (C-8) (37.34 mg, 55.83 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL)at 0 °C was added DIPEA (30.93 mg, 239.29 μmol, 41.68 μL) followed by HATU (45.49 mg, 119.64 μmol) portion wise. After 5 minutes, [5-[[[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (60 mg, 79.76 μmol, hydrochloric acid) was added. Then reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of starting material the reaction mixture was quenched with ice-cold water (5 mL), solid was obtained. Then filtered the solid and dried under reduced pressure to afford crude product (60 mg). The crude product (60 mg) was purified by Prep-HPLC to afford 3-[5-[1-[12-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1- methyl-pyrazole-3-carbonyl]piperazin-1-yl]-12-oxo-dodecanoyl]-4-piperidyl]-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (Compound 44) (29 mg, 21.28 μmol, 26.68% yield, 95.29% purity, formic acid)) as an off-white solid. Prep. HPLC condition: Column Name: C18; 150 x 20 mm; 5μ; Mobile Phase-A: 0.10 % FA in Water; Mobile Phase-B: Acetonitrile; Gradient program: (T/%B) 0/35, 3/35, 7/35, 7/70, 9/70, 9.1/95, 11/95, 11.1/35, 12/35; Flow Rate (mL/minute): 18; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1252.81 [M+H]⁺; Retention time (min): 1.69; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (bs, 1H), 9.86 (bs, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.10 (s, 1H), 7.04–6.99 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 5.40–5.22 (m, 2H), 4.84 (d, J = 8.4 Hz, 2H), 4.57 (d, J = 7.6 Hz, 1H), 4.15 (d, J = 7.2 Hz, 1H), 4.08 (d, J = 7.2 Hz, 1H), 4.06–3.89 (m, 6H), 3.66–3.45 (m, 6H), 3.33 (bs, 2H), 3.12–2.98 (m, 4H), 2.92–2.56 (m, 8H), 2.34 (bs, 4H), 2.23–1.96 (m, 5H) 190–170 (m 5H) 158–137 (m 6H) 226 (s 12H), (t, J = 7.2 Hz, 3H). Synthesis 45: Synthesis of 3-[4-[1-2-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo- ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 45): To a stirred solution of 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-1-piperidyl]acetic acid (C-22) (33.51 mg, 65.14 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) at 0 °C was added HATU (53.07 mg, 139.59 μmol) followed by DIPEA (36.08 mg, 279.17 μmol, 48.63 μL). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (70 mg, 93.06 μmol, hydrochloric acid) was added. Then the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by LCMS. After completion of starting material, the reaction mixture was quenched with ice-cold water (10 mL) sol nder reduced pressure to afford crude product. The crude product was purified by Prep-HPLC to afford 3-[4-[1-2-[4-[5- [[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol- 1-yl]piperidine-2,6-dione (Compound 45) (13.8 mg, 11.52 μmol, 12.38% yield, 95.52% purity, formic acid) as an off-white solid. Prep. HPLC condition: Column/dimensions: Sunfire C18 (19*150, 5μm); Mobile phase A: 0.2% Formic acid in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/10,1/10,12.50/30,12.55/98,16/98,16.10/10,19/10; Flow rate: 17 mL/min; Solubility: ACN+THF+water; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1098.65 [M+H]⁺; Retention time (min): 4.65; ¹H NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H), 9.59 (bs, 1H), 9.35 (s, 1H), 7.77–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.36–7.32 (m, 2H), 7.04– 6.93 (m, 4H), 6.65 (s, 1H), 5.44–5.22 (m, 2H), 4.84 (bs, 2H), 4.15 (d, J = 7.2 Hz, 1H), 4.08 (d, J = 7.2 Hz, 1H), 4.06–3.84 (m, 5H), 3.69–3.44 (bs, 7H), 3.29–2.78 (m, 11H), 2.69–2.53 (m, 2H), 2.34–1.92 (m, 8H), 1.90–1.67 (m, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 46: Synthesis of 3-[4-[1-[4-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-4-oxo- butanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 46):

To a stirred solution of 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-1-piperidyl]-4-oxo-butanoic acid (C-9) (36.25 mg, 65.14 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (36.08 mg, 279.17 μmol, 48.63 μL) followed by HATU (56.61 mg, 148.89 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (70 mg, 93.06 μmol, hydrochloric acid) was added. Then reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of starting material, the reaction mixture was quenched with ice-cold water (10 mL), solid was obtained. Then filtered the solid and dried under reduced pressure to afford crude (62 mg). The crude (62 mg) was purified by Prep-HPLC to afford 3-[4-[1-[4-[4-[5- [[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazole-3-carbonyl]piperazin-1-yl]-4-oxo-butanoyl]-4-piperidyl]-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (Compound 46) (15 mg, 12.55 μmol, 13.49% yield, 95.41% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18; Mobile phase A: 5 mM Ammonium bicarbonate in water; Mobile phase B: ACN; Gradient (Time/%B): 0/20, 2/20, 10/50, 15/50, 12.01/20, 15.0/100; Flow rate: 18 mL/min; Solubility: H2O+ACN; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1140.68 [M+H]⁺; Retention time (min): 1.46; ¹H NMR (400 MHz, DMSO-d6): δ 11.50–10.70 (bs, 1H), 9.29 (s, 1H), 7.178–7.69 (m, 1H), 7.34–7.27 (m, 2H), 7.09 (s, 1H), 7.00–6.95 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.60 (s, 1H), 5.38–5.22 (m, 2H), 4.81 (q, J = 8.8, 4.4 Hz, 2H), 4.55 (d, J = 6.8 Hz, 1H), 4.15 (d, J = 7.2 Hz, 1H), 4.09–3.88 (m, 6H), 3.69–3.47 (m, 6H), 3.33 (bs, 3H), 3.16–2.91 (m, 5H), 2.80–2.68 (m, 4H), 2.64–2.50 (m, 5H), 2.17–1.91 (m, 6H), 1.86–1.58 (m, 8H), 1.51 (bs, 2H), 0.71 (t, J = 7.2 Hz 3H) Synthesis 47: Synthesis of 3-[4-[1-[6-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-6-oxo- hexanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 47): To a stirred solution of 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-1-piperidyl]-6-oxo-hexanoic acid (C-10) (38.08 mg, 65.14 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (36.08 mg, 279.17 μmol, 48.63 μL) followed by HATU (53.07 mg, 139.59 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (70 mg, 93.06 μmol, hydrochloric acid) was added. Then reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by LCMS. After completion of starting material the reaction mixture was quenched with ice-cold water (10 mL) solid was obtained. Then filtered the solid and dried under reduced pressure to afford crude. The crude was purified by Prep-HPLC to afford 3-[4-[1-[6-[4-[5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3- carbonyl]piperazin-1-yl]-6-oxo-hexanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1- yl]piperidine-2,6-dione (Compound 47) (9.5 mg, 7.89 μmol, 8.48% yield, 97.01% purity) as an off-white solid. Prep. HPLC condition: Column: X-Bridge C185 um (4.6 mm*150 mm); Mobile Phase A: 10 mM Ammonium acetate in water; Mobile Phase B: 100% ACN; Gradient (T%B): 0/108/9511.0/95, 12.0/10, 15.0/10; Flow Rate: 1.0 mL/min; Sample Diluent: ACN+Water; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1168.69 [M+H]⁺; Retention time (min): 1.46; ¹H NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H), 9.57 (bs, 1H), 9.33 (s, 2H), 7.77–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.36–7.32 (m, 2H), 7.04–6.93 (m, 4H), 6.64 (s, 1H), 5.44–5.22 (m, 2H), 4.84 (bs, 2H), 4.15 (d, J = 7.2 Hz, 1H), 4.08 (d, J = 7.2 Hz, 1H), 4.06–3.84 (m, 7H), 3.69–3.44 (bs, 9H), 3.29–2.78 (m, 6H), 2.69–2.53 (m, 4H), 2.34–1.92 (m, 5H), 1.90–1.67 (m, 12H), 1.49 (bs, 4H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 48: Synthesis of 3-[4-[1-[10-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-10-oxo- decanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 48):

To a stirred solution of 10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 4-yl]-1-piperidyl]-10-oxo-decanoic acid (C-11) (34.30 mg, 53.55 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (36.08 mg, 279.17 μmol, 48.63 μL) followed by HATU (53.07 mg, 139.59 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (70 mg, 93.06 μmol, hydrochloric acid) was added. Then the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was monitored by LCMS. After completion of starting material the reaction mixture was quenched with ice-cold water (10 mL) and solid was obtained. Then filtered the solid and dried under reduced pressure to afford crude. Then crude was purified by Prep-HPLC to afford 3-[4-[1-[10-[4-[5-[[[7-(8-ethyl- 7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazole-3-carbonyl]piperazin-1-yl]-10-oxo-decanoyl]-4-piperidyl]-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (Compound 48) (40 mg, 30.53 μmol, 32.80% yield, 93.44% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18; Mobile phase A: 5 mM Ammonium acetate in water, Mobile phase B: ACN; Gradient (Time/%B): 0/10, 2/10,/40, 12/40, 13/100, 16/100.2, 16.1/10, 19/10; Flow rate: 18 mL/min; Solubility: H2O+ACN; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1224.79 [M+H]⁺; Retention time (min): 1.59; ¹H NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H), 9.57 (bs, 1H), 9.34 (s, 1H), 7.77–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.36–7.32 (m, 2H), 7.01–6.94 (m, 4H), 6.64 (s, 1H), 5.44–5.22 (m, 2H), 4.84 (bs, 2H), 4.15 (d, J = 7.2 Hz, 1H), 4.08 (d, J = 7.2 Hz, 1H), 4.06–3.84 (m, 7H), 3.69–3.44 (bs, 9H), 3.29–2.78 (m, 7H), 2.69–2.53 (m, 2H), 2.34–2.28 (m, 6H), 2.20–1.92 (m, 6H), 1.78–1.58 (m, 10H), 1.52 (bs, 9H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 49: Synthesis of 3-(4-(1-(12-(4-(5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-methyl-1H-pyrazole-3- carbonyl)piperazin-1-yl)-12-oxododecanoyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound 49): To a stirred solution of 12-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 4-yl]-1-piperidyl]-12-oxo-dodecanoic acid (C-12) (31.11 mg, 46.53 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (25.77 mg, 199.41 μmol, 34.73 μL) followed by HATU (37.91 mg, 99.70 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (50 mg, 66.47 μmol, hydrochloric acid) was added. Then reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of starting material, the reaction mixture was quenched with ice-cold water (5 mL), solid was obtained. Then the solid was filtered and dried under reduced pressure to afford crude (60 ) Th d (60 ) ifi d b P HPLC to afford 3-[4-[1-[12- [4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazole-3-carbonyl]piperazin-1-yl]-12-oxo-dodecanoyl]-4-piperidyl]-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (Compound 49) (18 mg, 13.79 μmol, 20.75% yield, 99.51% purity, formic acid) as an off-white solid. Prep. HPLC condition: Column Name: C18; 150 x 20 mm; 5μ; Mobile Phase-A: 0.10 % Formic acid in water; Mobile Phase-B: Acetonitrile; Gradient program: (T/%B) 0/30, 2/30, 10/40, 12/40, 13/100, 16/100; Flow Rate (mL/minute):18; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1252.81 [M+H]⁺; Retention time (min): 1.69; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 10.1 (bs, 1H), 9.54 (bs, 1H), 9.34 (s, 1H), 7.77–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.37–7.32 (m, 2H), 6.99–6.95 (m, 4H), 6.63 (s, 1H), 5.40–5.22 (m, 2H), 4.86 (bs, 2H), 4.57 (d, J = 7.6 Hz, 1H), 4.15 (d, J = 7.2 Hz, 1H), 4.08 (d, J = 7.2 Hz, 1H), 4.06–3.89 (m, 5H), 3.64–3.45 (m, 10H), 3.26–2.98 (m, 5H), 2.92–2.56 (m, 4H), 2.34 (bs, 6H), 2.18–1.96 (m, 5H), 1.90–1.70 (m, 5H), 1.66 (bs, 1H), 1.57–1.38 (m, 5H), 1.26 (s, 12H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 50: Synthesis of N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-5-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-5-oxo-pentanamide (Compound 50): O O NH N _NH N N O H N HO N O O ^O F HN C-13 N N HATU, DIPEA, DMF, RT, 12h N O N Step-1 F OH F A-4

To a stirred solution 5-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methylamino]-5-oxo-pentanoic acid (C-13) (31.52 mg, 58.65 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (36.08 mg, 279.17 μmol, 48.63 μL) followed by HATU (53.07 mg, 139.59 μmol). After 5 min at room temperature, [5-[[[7-(8-ethyl- 7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazol-3-yl]-piperazin-1-yl-methanone (A-4) (70 mg, 93.06 μmol, hydrochloric acid) was added. The reaction mixture was stirred at 25 °C for 12 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtain crude compound. The crude was purified by Prep-HPLC to afford N-[[1-(2,6-dioxo-3-piperidyl)- 2-oxo-benzo[cd]indol-6-yl]methyl]-5-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-5-oxo- pentanamide (Compound 50) (27 mg, 23.84 μmol, 25.61% yield, 98.98% purity) as off-white solid. Prep-HPLC condition: Column/dimensions : X- SELECT C18 (250*19) 5μ; Mobile phase A: 0.1% Formic acid in water (aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/20, 2/20, 7/40, 25/40, 35/100; Flow rate: 17 mL/min; Solubility: Acetonitrile+THF+water; Spot visualization: UV active compound; LCMS [ES⁺]: 1121.48 [M+H]⁺; Retention time (min): 1.45; ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (bs, 1H), 9.96 (bs, 1H), 9.48 (bs, 1H), 9.33 (s, 1H), 8.38–8.32 (m, 2H), 8.09 (d, J = 6.4 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.77–7.73 (m, 1H), 7.43–7.31 (m, 3H), 7.09 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 6.64 (s, 1H), 5.47 (dd, J = 7.2, 3.2 Hz, 1H), 5.38–5.21 (m, 1H), 4.92–4.78 (q, J = 10.6, 5.6 Hz, 2H), 4.67 (d, J = 6.4 Hz, 1H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 4.02–3.82 (m, 5H), 3.62–3.44 (bs, 8H), 3.18–2.89 (m, 4H), 2.88–2.61 (bs, 3H), 2.32 (bs, 2H), 2.18–1.96 (m, 7H), 1.89–1.73 (m, 5H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 51: Synthesis of N-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2- dihydrobenzo[cd]indol-6-yl)methyl)-7-(4-(5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-methyl-1H-pyrazole-3- carbonyl)piperazin-1-yl)-7-oxoheptanamide (Compound 51): To a stirred solution of [5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1-yl-methanone (A-4) (70 mg, 93.06 μmol, hydrochloric acid) and 7-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methylamino]- 7-oxo-heptanoic acid (C-14) (34.21 mg, 60.49 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (36.08 mg, 279.17 μmol, 48.63 μL) followed by HATU (53.07 mg, 139.59 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was monitored by TLC and LCMS. To the crude water was added water (5 mL) to afford a solid. A solid was filtered to afford crude product. The crude was purified by Prep-HPLC to obtain the product N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo- benzo[cd]indol-6-yl]methyl]-7-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-7-oxo-heptanamide (Compound 51) (20 mg, 16.54 μmol, 17.77% yield, 95.04% purity) as an yellow solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18; Mobile phase A: 5 mM Ammonium bicarbonate in water; Mobile phase B: ACN; Gradient (Time/%B): 0/10, 2/10, 10/40, 14/40, 14.1/98, 17.0/98, 17.01/10, 20/10; Flow rate: 18 mL/min; Solubility: H2O+ACN; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1147.48 [M+H]⁺; Retention time (min): 1.49; ¹H NMR (400 MHz, DMSO-d6): δ 11.11 (bs, 1H), 9.60 (bs, 1H), 9.34 (s, 1H), 8.36–8.32 (m, 2H), 8.10 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.77–7.73 (m, 1H), 7.41–7.26 (m, 3H), 7.08 (d, J = 8.0 Hz, 1H), 6.99 (s, 1H), 6.64 (s, 1H), 5.44 (d, J = 6.4 Hz, 1H), 5.36–5.22 (m, 1H), 4.84 (d, J = 8.4 Hz, 2H), 4.57 (d, J = 7.6 Hz, 1H), 4.15 (d, J = 7.2 Hz, 1H), 4.08 (d, J = 7.2 Hz, 1H), 4.06–3.89 (m, 5H), 3.66–3.45 (m, 3H), 3.12–2.98 (m, 5H), 2.92–2.56 (m, 4H), 2.34 (bs, 3H), 2.16–1.96 (m, 5H), 1.90–1.68 (m, 8H), 1.58–1.37 (m, 4H), 1.26 (s, 2H), (t, J = 7.2 Hz, 3H). Synthesis 52: Synthesis of N-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2- dihydrobenzo[cd]indol-6-yl)methyl)-10-(4-(5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-

yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-1-methyl-1H-pyrazole-3- carbonyl)piperazin-1-yl)-10-oxodecanamide (Compound 52): To a stirred solution of [5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1-yl-methanone (A-4) (70 mg, 93.06 μmol, hydrochloric acid) and 10-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methylamino]-10-oxo-decanoic acid (C-15) 36.75 mg, 60.49 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (36.08 mg, 279.17 μmol, 48.63 μL) followed by HATU (53.07 mg, 139.59 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was monitored by TLC and LCMS. To the crude water was added water (5 mL) to afford solid. A solid was filtered to afford crude product. The crude was purified by Prep-HPLC to obtain the product N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-10-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-10-oxo-decanamide (Compound 52) (26 mg, 20.00 μmol, 21.49% yield, 95.17% purity, formic acid) as a yellow solid. Prep. HPLC condition: Column/dimensions: X-SELECT- C18; Mobile phase A: 0.1% Formic acid in water; Mobile phase B: ACN; Gradient (Time/%B): 0/30, 2/30, 9/41, 13/41, 15/100, 15/100, 15.1/30, 18/30; Flow rate: 18 mL/min; Solubility: H2O+ACN+THF; Spot visualization: UV active compound; LCMS [ES-]: m/z 1189.56 [M-H]-; Retention time (min): 1.58; ¹H NMR (400 MHz, DMSO-d6): δ 11.10 (bs, 1H), 9.86 (bs, 1H), 9.36 (s, 1H), 8.36–8.32 (m, 2H), 8.10 (d, J = 7.2 Hz, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.77–7.73 (m, 1H), 7.41–7.26 (m, 3H), 7.09 (d, J = 7.2 Hz, 1H), 6.99 (s, 1H), 6.64 (s, 1H), 5.44 (d, J = 6.4 Hz, 1H), 5.36–5.22 (m, 1H), 4.84 (d, J = 8.4 Hz, 2H), 4.57 (d, J = 7.6 Hz, 1H), 4.15 (d, J = 7.2 Hz, 1H), 4.08 (d, J = 7.2 Hz, 1H), 4.06–3.89 (m, 5H), 3.66–3.45 (m, 6H), 3.12–2.98 (m, 4H), 2.92–2.56 (m, 3H), 2.34 (bs, 3H), 2.19–1.96 (m, 7H), 1.90–1.70 (m, 5H), 1.58–1.37 (m, 4H), 1.28 (s, 8H), (t, J = 7.2 Hz, 3H). Synthesis 53: Synthesis of N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-12-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-12-oxo-dodecanamide (Compound 53):

To a stirred solution of 12-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methylamino]-12-oxo-dodecanoic acid (C-16) (43.51 mg, 68.46 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (37.92 mg, 293.39 μmol, 51.10 μL) followed by HATU (59.50 mg, 156.48 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (70 mg, 97.80 μmol) was added. Then reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was monitored by LCMS. After completion of starting material, the reaction mixture was quenched with ice-cold water (10 mL), solid was obtained. Then the solid was filtered and dried under reduced pressure to afford crude (60 mg). The crude (60 mg) was purified by Prep-HPLC to afford N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo- benzo[cd]indol-6-yl]methyl]-12-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-12-oxo-dodecanamide (Compound 53) (19 mg, 15.10 μmol, 15.44% yield, 96.92% purity) as a yellow solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18; Mobile phase A: 5 mM Ammonium bicarbonate in water; Mobile phase B: ACN; Gradient (Time/%B): 0/20, 2/20, 10/50, 15/50, 12.01/20, 15.0/100; Flow rate: 18 mL/min; Solubility: H₂O+ACN; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1219.66 [M+H]⁺; Retention time (min): 1.66; ¹H NMR (400 MHz, DMSO-d6): δ 10.49–10.20 (bs, 1H), 9.29 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.32 (t, J = 7.6 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.84 (t, J = 7.2 Hz, 1H), 7.75–7.72 (m, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.35–7.29 (m, 2H), 7.08 (d, J = 7.2 Hz, 1H), 6.98 (s, 1H), 6.62 (s, 1H), 5.44–5.19 (m, 2H), 4.91–4.26 (q, J = 8.8, 4.4 Hz, 2H), 4.68 (d, J = 7.2 Hz, 2H), 4.15 (d, J = 7.2 Hz, 1H), 4.07 (d, J = 7.2 Hz, 1H), 4.06–3.84 (m, 5H), 3.63–3.39 (m, 7H), 3.14–2.88 (m, 4H), 2.83–2.53 (m, 4H), 2.38 (bs, 2H), 2.19–1.89 (m, 8H), 2.88–2.70 (m, 3H), 1.44 (bs, 4H), 1.29–1.09 (bs, 12H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 54: Synthesis of 3-[6-[1-[2-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo- ethyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 54): To a stirred solution of 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1- piperidyl]acetic acid (C-23) (23.19 mg, 46.53 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (25.77 mg, 199.41 μmol, 34.73 μL) followed by HATU (37.91 mg, 99.70 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (50 mg, 66.47 μmol, hydrochloric acid) was added. Then the reaction mixture was stirred at room temperature for 16 hours The reaction progress was monitored by LCMS. After completion, the reaction mixture was lyophilized to obtain crude compound. The crude was purified by Prep-HPLC to afford the product 3-[6-[1-[2-[4-[5-[[[7-(8-ethyl-7-fluoro- 3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3- carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 54) (10 mg, 8.65 μmol, 13.02% yield, 97.64% purity, formic acid) as an off-white solid. Prep. HPLC condition: Column/dimensions: X select 19*250mm, 5μm; Mobile phase A: 0.1% formic acid in water; Mobile phase B: 100% ACN; Gradient (Time/%B): 0/10, 2/10, 10/28, 14/28, 14.1/100; Flow rate: 17 mL/min; Solubility: Water+THF+ACN; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1082.48 [M+H]⁺; Retention time (min): 1.29.¹H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 10.42–9.86 (bs, 1H), 9.57 (bs, 1H), 9.34 (s, 1H), 7.78–7.73 (q, J = 9.2, 6.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.38–7.29 (m, 2H), 7.05–6.98 (m, 2H), 6.65 (s, 1H), 5.35–5.28 (m, 1H), 4.91–4.78 (m, 2H), 4.34–4.28 (m, 1H), 4.16–3.93 (m, 10H), 3.66 (bs, 6H), 3.22 (bs, 2H), 3.12–2.77 (m, 9H), 2.35 (bs, 1H), 2.18–1.96 (m, 8H), 1.88– 1.69 (m, 7H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 55: Synthesis of 3-[4-[1-[2-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo- ethyl]-4-piperidyl]phenyl]piperidine-2,6-dione (Compound 55):

To a stirred solution of 2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]acetic acid (1) (20.68 mg, 46.53 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (25.77 mg, 199.41 μmol, 34.73 μL) followed by HATU (37.91 mg, 99.70 μmol). After 5 minutes, [5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1-yl-methanone (A-4) (50 mg, 66.47 μmol, hydrochloric acid) was added. Then the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by LCMS. After completion, the reaction mixture was lyophilized to obtain crude compound. The crude was purified by Prep-HPLC to afford the product 3-[4-[1-[2-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4- piperidyl]phenyl]piperidine-2,6-dione (Compound 55) (10 mg, 8.48 μmol, 12.76% yield, 96.90% purity, trifluoroacetic acid) as an off-white solid. Prep. HPLC condition: Column/dimensions: X select 19*250 mm, 5 μm; Mobile phase A: 0.1% Formic acid in water; Mobile phase B: 100% ACN; Gradient (Time/%B): 0/10, 2/10, 10/28, 14/28, 14.1/100; Flow rate: 17 mL/min; Solubility: Water+THF+ACN; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1028.47 [M+H]⁺; Retention time (min): 1.29; ¹H NMR (400 MHz, DMSO- d6): δ 10.81 (s, 1H), 9.93 (s, 1H), 9.62 (bs, 1H), 9.37 (s, 1H), 7.80–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.38–7.33 (m, 2H), 7.26–7.15 (m, 4H), 6.99 (d, J = 2.4 Hz, 1H), 6.70 (bs, 1H), 5.78–5.14 (m, 1H), 4.87 (bs, 2H), 4.67–3.97 (m, 8H), 3.85–3.42 (m, 9H), 3.27–2.72 (m, 8H), 2.62 (bs, 2H), 2.36 (bs, 1H), 2.22–1.71 (m, 13H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 56: Synthesis of 3-[4-[1-[2-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo- ethyl]-4-piperidyl]phenoxy]piperidine-2,6-dione (Compound 56): To a stirred solution 2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]-1-piperidyl]acetic acid (C-18) (24.48 mg, 53.18 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1mL) at 0 °C was added DIPEA (25.77 mg, 199.41 μmol, 34.73 μL) followed by HATU (37.91 mg, 99.70 μmol). After 5 min at room temperature was added [5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1- yl-methanone (A-4) (50 mg, 66.47 μmol, hydrochloric acid). The reaction mixture was stirred at 25°C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilised to obtain crude compound. The crude was purified by Prep-HPLC to afford 3-[4-[1-[2-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4- piperidyl]phenoxy]piperidine-2,6-dione (Compound 56) (11 mg, 10.08 μmol, 15.16% yield, 95.66% purity) as an off-white solid. Prep-HPLC condition: Column Name: X BRIDGE C18; 150 x 20 mm; 5 μ; Mobile Phase-A: 5 mM Ammonium acetate in qater; Mobile Phase-B: Acetonitrile; Gradient program (T/%B): 0/15, 2/15, 10/45, 14/45, 14.01/98, 17.01,98, 17.02/15; Flow Rate (mL/minute): 17; Sample Loading (mg/Injection): 60; No. of Injection's: 15; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1044.4 [M+H]⁺; Retention time (min): 2.58; ¹H NMR (400 MHz, DMSO-d6): δ 10.87 (bs, 1H), 9.69 (bs, 1H), 9.35 (s, 1H), 7.77–7.72 (q, J = 9.2, 6.0 Hz, 1H), 7.36–7.28 (m, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 2.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.68–6.59 (m, 1H), 5.34–5.12 (m, 2H), 4.92–4.78 (m, 2H), 4.17–3.91 (m, 7H), 3.64 (bs, 3H), 3.49 (bs, 2H), 3.18 (bs, 2H), 3.12–2.39 (m, 10H), 2.21–1.93 (m, 9H), 1.85–1.55 (m, 8H), 0.70 (t, J = 7.6 Hz, 3H). Synthesis 57: Synthesis of 3-[7-[1-[2-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo- ethyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 57): To stirred solution of [5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]- A-4) (50 mg, 66.47 μmol, hydrochloric acid) and 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-7-yl]-1- piperidyl]acetic acid (C-24) (26.51 mg, 53.18 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) at room temperature was added HATU (37.91 mg, 99.70 μmol) followed by DIPEA (25.77 mg, 199.41 μmol, 34.73 μL). The reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) solid was precipitated. A solid was filtered to afford crude product. The crude was purified by prep-HPLC to afford product 3-[7-[1-[2-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-1- methyl-indazol-3-yl]piperidine-2,6-dione (Compound 57) (13 mg, 11.63 μmol, 17.49% yield, 96.79% purity)as an off-white solid. Prep. HPLC condition: Column Name: X-SELECT C18; 250 x 19mm; 5 μ; Mobile Phase-A: 0.10 % Formic acid in water; Mobile Phase-B: Acetonitrile; Gradient program (T/%B): 0.1/10, 3/10, 7/35, 10/30, 10.10/95, 13/95; Flow Rate (mL/minute): 18. No. of Injection's:12; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1082.39 [M+H]⁺; Retention time (min): 5.49; ¹H NMR (400 MHz, DMSO-d6): δ 10.87 (bs, 1H), 9.92 (s, 1H), 9.48 (bs, 1H), 9.33 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.37–7.31 (m, 2H), 7.25 (bs, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.65 (bs, 1H), 5.34–5.18 (m, 1H), 4.92–4.78 (m, 2H), 4.37–4.32 (m, 1H), 4.22–3.93 (m, 10H), 3.71–3.49 (m, 6H), 3.24 (bs, 3H), 3.15–2.96 (m, 5H), 2.88–2.77 (m, 1H), 2.67–2.56 (m, 3H), 2.32–2.22 (m, 5H), 2.19–1.98 (m, 5H), 1.92–1.73 (m, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 58: Synthesis of 1-[4-[1-[2-[4-[5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]amino]methyl]-1-methyl-pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo- ethyl]-4-piperidyl]phenyl]hexahydropyrimidine-2,4-dione (Compound 58):

To stirred solution of [5-[[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]amino]methyl]-1-methyl-pyrazol-3-yl]-piperazin-1-yl-methanone (A-4) (50 mg, 66.47 μmol, hydrochloric acid) and 2-[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-1-piperidyl]acetic acid (C-28) (20.72 mg, 46.53 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) at room temperature was added HATU (37.91 mg, 99.70 μmol) followed by DIPEA (25.77 mg, 199.41 μmol, 34.73 μL). The reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) solid was precipitated. A solid was filtered to afford crude product. The crude was purified by prep-HPLC to afford product 1-[4-[1-[2-[4-[5-[[[7-(8-ethyl- 7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]amino]methyl]-1-methyl- pyrazole-3-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]phenyl]hexahydropyrimidine- 2,4-dione (Compound 58) (7 mg, 6.76 μmol, 10.16% yield, 99.32% purity) as an off-white solid. Prep. HPLC condition: Column Name: X-SELECT C18; 250 x 19 mm, 5 μm; Mobile Phase-A: 0.10 % Formic acid in water; Mobile Phase-B: Acetonitrile, Gradient program (T/%B): 0.1/10, 3/10, 7/35, 10/30, 10.10/95, 13/95; Flow Rate (mL/minute): 18; No. of Injection's:12; Spot visualization: UV active compound. LCMS [ES⁺]: m/z 1029.50 [M+H]⁺; Retention time (min): 5.40; ¹H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.93 (s, 1H), 9.49 (bs, 1H), 9.33 (s, 1H), 7.79–7.74 (q, J = 8.8, 6.4 Hz, 1H), 7.37–7.31 (m, 2H), 7.28–7.21 (m, 4H), 6.99 (s, 1H), 6.64 (s, 1H), 5.34–5.22 (m, 1H), 4.93–4.79 (m, 2H), 4.15 (d, J = 10.8 Hz, 1H), 4.08 (d, J = 10.4 Hz, 2H), 4.06 (bs, 4H), 3.74 (t, J = 6.8 Hz, 2H), 3.64 (bs, 4H), 3.50 (bs, 2H), 3.19 (bs, 2H), 3.14– 2.99 (m, 3H), 2.96–2.88 (m, 2H), 2.84–2.64 (m, 2H), 2.39 (bs, 1H), 2.14–1.95 (m, 7H), 1.87– 1.72 (m, 6H), 1.63 (bs, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 59: Synthesis of 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-2- oxo-ethyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 59): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (A-5) (70 mg, 94.36 μmol) and 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetic acid (C-17) (32.59 mg, 94.36 μmol) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (60.98 mg, 471.82 μmol, 82.18 μL) followed by HATU (53.82 mg, 141.55 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, reaction mixture was lyophilized to afford crude which was purified by prep- HPLC to afford 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4- piperidyl]anilino]piperidine-2,6-dione (Compound 59) (21 mg, 19.02 μmol, 20.15% yield, 96.82% purity) as off-white solid. Prep. HPLC condition: Column/dimensions: X-SELECT C18 (150*19*5 μ); Mobile phase A: 5mM Ammonium acetate in water (aq); Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/25, 2/25, 8/52, 14/52, 14.01/100; Flow rate: 18 mL/min; Solubility: ACN+THF+water; Spot visualization: UV active compound; LCMS [ES⁺]: 1069.60 [M+H] ⁺; Retention time (min): 1.36; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 10.02 (bs, 1H), 9.14 (s, 1H), 8.21 (s, 1H), 7.77–7.73 (q, J = 9.2, 6.0 Hz, 1H), 7.36–7.32 (m, 2H), 7.01 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 5.66 (d, J = 7.6 Hz, 1H), 5.38–5.21 (m, 1H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.38–4.29 (m, 3H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.83–3.52 (m, 7H), 3.19 (s, 2H), 3.16–2.97 (m, 4H), 2.93–2.77 (m, 6H), 2.72–2.54 (m, 2H), 2.32 (s, 2H), 2.19–1.95 (m, 8H), 1.88–1.72 (m, 4H), 1.66 (bs, 2H), 1.54 (bs, 2H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 60: Synthesis of 3-[4-[1-[4-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-4- oxo-butanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 60): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (A-5) (70 mg, 89.94 μmol, hydro hl i id) d ( di i id l) ino]phenyl]-1-piperidyl]- 4-oxo-butanoic acid (C-1) (31.57 mg, 62.96 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (58.12 mg, 449.72 μmol, 78.33 μL) followed by HATU (51.30 mg, 134.92 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, reaction mixture was lyophilized to afford crude which was purified by prep-HPLC to afford 3-[4-[1-[4- [4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-4-oxo-butanoyl]-4- piperidyl]anilino]piperidine-2,6-dione (Compound 60) (19 mg, 16.39 μmol, 18.22% yield, 95.84% purity) as off-white solid. Prep. HPLC condition: Column/dimensions: X-SELECT C18 (150*19*5 μ); Mobile phase A: 5mM Ammonium acetate in water (aq); Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/25, 2/25, 8/52, 14/52, 14.01/100; Flow rate: 18mL/min; Solubility: ACN+THF+water; Spot visualization: UV active compound; LCMS [ES⁺]: 1111.60 [M+H]⁺; Retention time (min): 1.56; ¹H NMR (400 MHz, DMSO-d6): δ 11.77 (bs, 1H), 9.13 (s, 1H), 8.22 (s, 1H), 7.77–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.36–7.32 (m, 2H), 7.01 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 5.66 (d, J = 7.2 Hz, 1H), 5.38–5.21 (m, 2H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.56 (d, J = 6.8 Hz, 1H), 4.33 (s, 3H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.98 (d, J = 8.4 Hz, 1H), 3.82–3.62 (m, 4H), 3.61–3.49 (m, 4H), 3.16–2.91 (m, 7H), 1.82–2.48 (m, 9H), 2.32 (bs, 1H), 2.19–1.95 (m, 7H), 1.89–1.63 (m, 6H), 1.52 (bs, 1H), 1.37 (bs, 1H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 61: Synthesis of 3-[4-[1-[7-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-7- oxo-heptanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 61):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (A-5) (0.07 g, 89.94 μmol, hydrochloric acid) and 7-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]- 7-oxo-heptanoic acid (36.49 mg, 62.96 μmol, trifluoroacetic acid) (C-2) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by HATU (51.30 mg, 134.92 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, ice-cold water (5 mL) was added to the reaction mixture to afford solid. A solid was filtered to afford crude product which was purified by prep-HPLC to afford 3-[4-[1-[7-[4-[5-[7-(8-ethyl-7-fluoro- 3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2- carbonyl]piperazin-1-yl]-7-oxo-heptanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 61) (27 mg, 23.13 μmol, 25.71% yield, 98.79% purity) as off-white solid. Prep. HPLC condition: Column/dimensions: X BRIDGE-C18 (19*250, 5μm); Mobile phase A: 5mM Ammonium acetate; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/40,2/40,10/60,10.01/100,12/100,12.01/40,15/40; Flow rate: 17 mL/min; Solubility: ACN+water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: 1153.64 [M+H] ⁺; Retention time (min): 1.60; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (bs, 1H), 9.96 (bs, 1H), 9.13 (s, 1H), 8.21 (s, 1H), 7.77–7.74 (q, J = 8.8, 6.4 Hz, 1H), 7.36–7.32 (m, 2H), 7.01 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.60 (d, J = 8.0 Hz, 2H), 5.67 (d, J = 7.6 Hz, 1H), 5.40–5.21 (m, 2H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.55 (d, J = 6.8 Hz, 1H), 4.33 (s, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 56 Hz 1H) 393 (d J = 84 Hz 1H) 381 362 (m 4H), 3.54 (s, 4H), 3.16– 2.90 (m, 6H), 2.86–2.54 (m, 4H), 2.32 (s, 5H), 2.19–1.96 (m, 7H), 1.88–1.67 (m, 8H), 1.52 (bs, 5H), 1.33 (bs, 3H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 62: Synthesis of 3-[4-[1-[10-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]- 10-oxo-decanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 62): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (A-5) (70 mg, 89.94 μmol, hydrochloric acid) and 10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]-10-oxo-decanoic acid (C-3) (36.87 mg, 62.96 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (11.62 mg, 89.94 μmol, 15.67 μL) followed by HATU (34.20 mg, 89.94 μmol). The reaction mixture was stirred at 25 °C for 12 hours. The progress of reaction was monitored by TLC and LCMS. After completion, reaction mixture was lyophilized to afford crude which was purified by prep-HPLC to afford 3-[4-[1- [10-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahyd li i l h id d i idi -4-yl]-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-10-oxo-decanoyl]-4- piperidyl]anilino]piperidine-2,6-dione (Compound 62) (34 mg, 26.96 μmol, 29.98% yield, 98.44% purity, Formic acid) as off-white solid. Prep. HPLC condition: Column/dimensions: X- SELECT C18 (150*19*5 μ); Mobile phase A: 0.1% Formic acid in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/25, 2/25, 8/48, 11/48, 11.01/100, 14/100, 14.01/25; Flow rate: 18 mL/min; Solubility: Acetonitrile+THF+water; Spot visualization: UV active compound; LCMS [ES⁺]: 1195.71 [M+H]⁺; Retention time (min): 1.72; ¹H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 10.02 (bs, 1H), 9.13 (s, 1H), 8.21 (s, 1H), 7.77–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.36– 7.32 (m, 2H), 7.01 (s, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 5.66 (d, J = 7.6 Hz, 1H), 5.38–5.21 (m, 1H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.56 (d, J = 6.8 Hz, 1H), 4.33 (s, 3H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.98 (d, J = 8.4 Hz, 1H), 3.82–3.62 (m, 4H), 3.61–3.49 (m, 4H), 3.16–2.91 (m, 6H), 2.82–2.48 (m, 6H), 2.32 (bs, 3H), 2.19–1.95 (m, 7H), 1.89–1.63 (m, 7H), 1.52 (bs, 5H), 1.37 (bs, 9H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 63: Synthesis of 3-[4-[1-[12-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]- 12-oxo-dodecanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 63):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (A-5) (70 mg, 89.94 μmol, hydrochloric acid) and 12-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]-12-oxo-dodecanoic acid (C-4) (38.64 mg, 62.96 μmol, trifluoroacetic acid) in N,N- dimethylformamide (2 mL) at 0 °C was added DIPEA (58.12 mg, 449.72 μmol, 78.33 μL) followed by HATU (51.30 mg, 134.92 μmol). The reaction mixture was stirred at 25 °C for 12 hours. The progress of reaction was monitored by TLC and LCMS. After completion, reaction mixture was lyophilized to afford crude which was purified by prep-HPLC to afford 3-[4-[1-[12- [4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-12-oxo-dodecanoyl]-4- piperidyl]anilino]piperidine-2,6-dione (Compound 63) (25 mg, 19.53 μmol, 21.71% yield, 99.17% purity, formic acid) as off-white solid. Prep. HPLC condition: Column/dimensions: X- SELECT C18 (150*19*5 μ); Mobile phase A: 0.1%; Formic acid in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/20, 2/20, 8/47, 12/47, 12.01/95, 15.1/20; Flow rate: 18mL/min; Solubility: ACN+THF+water; Spot visualization: UV active compound; LCMS [ES⁺]: 1223.73 [M+H]⁺; Retention time (min): 1.81; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 10.02 (bs, 1H), 9.13 (s, 1H), 8.22 (s, 1H), 7.77–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.36–7.32 (m, 2H), 7.10 (s, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 5.66 (d, J = 7.6 Hz, 1H), 5.38–5.21 (m, 2H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.56 (d, J = 6.8 Hz, 1H), 4.33 (s, 3H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.94 (d, J = 8.4 Hz, 1H), 3.78–3.62 (m, 4H), 3.54 (s, 4H), 3.16–2.89 (m, 6H), 2.76–2.56 (m, 4H), 2.33 (bs, 4H), 2.21–1.98 (m, 7H), 1.88– 1.68 (m, 8H), 1.48 (s, 5H), 1.27 (s, 12H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 64: Synthesis of 3-[5-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-2- oxo-ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 64): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (0.07 g, 89.94 μmol, hydrochloric acid) (A-5) 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-1-piperidyl]acetic acid (32.39 mg, 62.96 μmol, trifluoroacetic acid) (C-21) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by addition of HATU (51.30 mg, 134.92 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) to afford a solid precipitate. The precipitated solid was filtered to afford crude product which was purified by Prep-HPLC to afford3-[5-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-3- methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione) (Compound 64) (19 mg, 16.37 μmol, 18.20% yield, 96.85% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X BRIDGE-C18 (1 * ) bil h i acetate; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/40,2/40,10/60,10.01/100,12/100,12.01/40,15/40; Flow rate: 17 mL/min; Solubility: ACN+water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1124.64 [M+H]⁺; Retention time (min): 4.71; ¹H NMR (400 MHz, DMSO- d6): δ 10.07 (bs, 1H), 9.93 (bs, 1H), 9.14 (s, 1H), 8.22 (s, 1H), 7.77–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.36–7.32 (m, 2H), 7.07 (s, 1H), 7.01–6.91 (m, 2H), 6.90 (d, J = 8.4 Hz, 1H), 5.38–5.21 (m, 2H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.33 (s, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.87–3.52 (m, 8H), 3.44 (bs, 3H), 3.32 (s, 2H), 3.16–2.82 (m, 9H), 2.54 (bs, 2H), 2.21–1.96 (m, 10H), 1.82–1.63 (m, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 65: Synthesis of 3-[5-[1-[4-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-4- oxo-butanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 65): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (0.07 g, 94.36 μmol) (A-5) and 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]-4-oxo-butanoic acid (29.23 mg, 66.06 μmol) (C-5) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (30.49 mg, 235.91 μmol followed by addition of HATU (53.82 mg, 141.55 μmol) , 41.09 μL). Then the reaction mixture was stirred at 25 °C for 12 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to afford crude mass. The obtained crude mass was purified by prep-HPLC to afford 3-[5-[1-[4-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-4-oxo-butanoyl]-4-piperidyl]-3- methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 65) (29 mg, 24.66 μmol, 26.13% yield, 99.16% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X BRIDGE-C18 (19*250, 5 μm); Mobile phase A: 5 mM Ammonium acetate; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/20,2/20,10/40,12/40,12.01/100,13/100,13.01/40,15/40; Flow rate: 17 mL/min; Solubility: ACN+water+THF; Spot visualization: UV active compound. LCMS [ES⁺]: m/z 1166.41 [M+H]⁺; Retention time (min): 1.53 min; ¹H NMR (400 MHz, DMSO-d6): δ 11.17 (bs, 1H), 9.14 (s, 1H), 8.22 (s, 1H), 7.77–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.36– 7.32 (m, 2H), 7.10 (s, 1H), 7.03–6.92 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 5.38–5.21 (m, 2H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.56 (d, J = 6.8 Hz, 1H), 4.33 (s, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 4.08 (bs, 1H), 3.84–3.46 (m, 8H), 3.44 (bs, 3H), 3.16–2.80 (m, 8H), 2.73–2.52 (m, 7H), 2.32 (s, 1H), 2.21–1.92 (m, 7H), 1.78–1.68 (m, 7H), 1.52 (bs, 1H), 1.22 (s, 1H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 66: Synthesis of 3-[5-[1-[6-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-6-

oxo-hexanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 66): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (A-5) (70 mg, 89.94 μmol, hydrochloric acid) and 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexanoic acid (C-6) (36.80 mg, 62.96 μmol, trifluoroacetic acid)6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]-6-oxo-hexanoic acid (36.80 mg, 62.96 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.50 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by HATU (51.30 mg, 134.92 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. After completion, ice-cold water (5 mL) was added to the reaction mixture and lyophilized to afford crude The crude was purified by Prep-HPLC to obtain the product 3-[5-[1-[6-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-6-oxo- hexanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 66) (10 mg, 7.33 μmol, 8.15% yield, 95.85% purity, trifluoroacetic acid) as an off-white solid. Column Name: X-BRIDGE -C18(19*250, 5 μm); Mobile Phase-A: 5 mM Ammonium acetate in water; Mobile Phase-B: 100% CAN; Gradient (Time/%B): 0/20,2/20,10/45,17/45,17.1/98,20/98,20.1/20,22/20; Flow Rate: 17 mL/minute; Solubility: THF+ACN+Water; LCMS [ES⁺]: 1194.54 [M+H]⁺; Retention time (min): 1.53; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.13 (s, 1H), 8.21 (s, 1H), 7.78–7.73 (m, 1H), 7.37–7.31 (m, 2H), 7.10 (s, 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.4 Hz, 1H), 5.38–5.19 (m, 2H), 5.12– 4.98 (m, 2H), 4.59–4.53 (m, 1H), 4.32 (bs, 2H), 4.21–3.96 (m, 3H), 3.77 (bs, 4H), 3.55 (bs, 4H), 3.32 (s, 3H), 3.15–3.02 (m, 4H), 2.97–2.76 (m, 5H), 2.68–2.57 (m, 3H), 2.43–2.32 (m, 3H), 2.22–1.97 (m, 7H), 1.86–1.74 (m, 5H), 1.68 (bs, 2H), 1.54 (bs, 6H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 67: Synthesis of 3-[5-[1-[10-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]- 10-oxo-decanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 67):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (0.07 g, 89.94 μmol, hydrochloric acid) (A-5) and 10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-10-oxo-decanoic acid (40.34 mg, 62.96 μmol, trifluoroacetic acid) (C-7) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by addition of HATU (51.30 mg, 134.92 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL), solid precipitate was observed. The precipitated solid was filtered and dried to obtain crude. The obtained crude was purified by Prep-HPLC to afford 3-[5-[1-[10-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-10- oxo-decanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 67) (21 mg, 15.58 μmol, 17.32% yield, 96.17% purity, Formic acid) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-SELECT C18 (150*19*5 μ); Mobile phase A: 0.1% Formic acid in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/20, 2/20, 8/47, 12/47, 12.01/95, 14/95; Flow rate: 18 mL/min; Solubility: ACN+water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1250.71 [M+H]⁺; Retention time (min): 1.68; ¹H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 10.10 (bs, 1H), 9.13 (s, 1H), 8.21 (s, 1H), 7.77–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.36–7.32 (m, 2H), 7.09 (s, 1H), 7.01–6.99 (m, 2H), 6.90 (d, J = 7.6 Hz, 1H), 5.38–5.21 (m, 2H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.56 (d, J = 6.8 Hz, 1H), 4.33 (s, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.98 (d, J = 8.4 Hz, 1H), 3.81–3.62 (m, 4H), 3.54 (s, 4H), 3.40 (bs, 3H), 3.16–3.01 (m, 3H), 2.98–2.66 (m, 8H), 2.62– 2.59 (m, 1H), 2.32 (s, 5H), 2.19–1.94 (m, 7H), 1.88–1.73 (m, 5H), 1.52 (bs, 6H), 1.27 (s, 8H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 68: Synthesis of 3-[5-[1-[12-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]- 12-oxo-dodecanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 68): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (0.07 g, 89.94 μmol, hydrochloric acid) (A-5) and 12-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-12-oxo-dodecanoic acid (42.10 mg, 62.96 μmol, trifluoroacetic acid) (C-8) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by addition of HATU (51.30 mg, 134.92 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) to afford solid precipitated. The precipitated solid was filtered to afford crude product which was purified by Prep-HPLC to afford 3-[5-[1-[12-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-12-oxo-dodecanoyl]- 4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 68) (15.5 mg, 11.39 μmol, 12.66% yield, 97.31% purity, formic acid) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-SELECT C18 (150*19*5 μ); Mobile phase A: 0.1% Formic acid in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/20, 2/20, 8/47, 12/47, 12.01/95, 14/95; Flow rate: 18 mL/min; Solubility: ACN+water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1278.65[M+H]⁺; Retention time (min): 1.77; ¹H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 10.02 (bs, 1H), 9.13 (s, 1H), 8.21 (s, 1H), 7.77–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.36–7.32 (m, 2H), 7.09 (s, 1H), 7.01–6.99 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 5.38–5.21 (m, 2H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.56 (d, J = 6.8 Hz, 1H), 4.33 (s, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.94 (d, J = 8.4 Hz, 1H), 3.78–3.62 (m, 4H), 3.54 (s, 4H), 3.34 (bs, 3H), 3.12–2.96 (m, 4H), 2.92–2.71 (m, 6H), 2.56 (bs, 3H), 2.32 (bs, 4H), 2.19–1.94 (m, 7H), 1.87–1.74 (m, 5H), 1.47 (bs, 6H), 1.26 (s, 12H) , 0.70 (t, J = 7.2 Hz, 3H). Synthesis 69: Synthesis of 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-2- oxo-ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 69):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (0.07 g, 89.94 μmol, hydrochloric acid) (A-5) 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 4-yl]-1-piperidyl]acetic acid (32.39 mg, 62.96 μmol, trifluoroacetic acid) (C-22) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by addition of HATU (51.30 mg, 134.92 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) to afford a solid precipitate. The precipitated solid was filtered to afford crude product which was purified by Prep-HPLC to afford 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-3- methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 69) (13 mg, 11.33 μmol, 12.60% yield, 97.97% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X BRIDGE-C18 (19*250, 5μm); Mobile phase A: 5 mM Ammonium acetate; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/40,2/40,10/60,10.01/100,12/100,12.01/40,15/40; Flow rate: 17 mL/min; Solubility: ACN+water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1124.64 [M+H]⁺; Retention time (min): 5.62; ¹H NMR (400 MHz, DMSO- d6): δ 10.77 (bs, 1H), 9.13 (s, 1H), 8.22 (s, 1H), 7.77–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.33–7.24 (m, 2H), 7.00–6.93 (m, 4H), 5.42–5.21 (m, 2H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.33 (bs, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.79–3.68 (m, 6H), 3.58 (s, 5H), 3.22 (bs, 3H), 3.16–2.92 (m, 4H), 2.91–2.78 (m, 6H), 2.58 (s, 2H), 2.32 (s, 1H), 2.22–1.92 (m, 9H), 1.87–1.69 (m, 7H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 70: Synthesis of 3-[4-[1-[4-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-4- oxo-butanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 70): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (0.07 g, 89.94 μmol, hydrochloric acid) (A-5) and 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-4-yl]-1-piperidyl]-4-oxo-butanoic acid (35.04 mg, 62.96 μmol, trifluoroacetic acid) (C-9) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by addition of HATU (51.30 mg, 134.92 μmol). Then reaction mixture was stirred at 25 °C for 12 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to afford crude product. The crude product was purified by Prep-HPLC to afford 3-[4-[1-[4-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy- 1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2- carbonyl]piperazin-1-yl]-4-oxo-butanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1- yl]piperidine-2,6-dione (Compound 70) (19 mg, 15.78 μmol, 17.54% yield, 96.83% purity) as off-white solid. Prep. HPLC condition: Column/dimensions: X BRIDGE-C18 (19*250, 5 μm); Mobile phase A: 5 mM Ammonium acetate; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/40, 2/40, 10/60, 10.01/100, 12/100, 12.01/40, 15/40; Flow rate: 17 mL/min; Solubility: ACN+water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1166.56 [M+H]⁺; Retention time (min): 1.52 min; ¹H NMR (400 MHz, DMSO-d6): δ 10.07 (bs, 1H), 9.14 (s, 1H), 8.22 (s, 1H), 7.77–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.36–7.32 (m, 2H), 7.03–6.99 (m, 4H), 5.42–5.21 (m, 2H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.56 (d, J = 6.8 Hz, 1H), 4.33 (s, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 4.08 (bs, 1H), 3.87–3.46 (m, 12H), 3.44 (bs, 1H), 3.16–2.82 (m, 7H), 2.73–2.52 (m, 7H), 2.32 (s, 1H), 2.21–1.92 (m, 8H), 1.78–1.68 (m, 5H), 1.52 (bs, 1H), 1.22 (s, 1H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 71: Synthesis of 3-[4-[1-[6-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-6- oxo-hexanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 71):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (0.07 g, 89.94 μmol, hydrochloric acid) (A-5) and 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-4-yl]-1-piperidyl]-6-oxo-hexanoic acid (36.80 mg, 62.96 μmol, trifluoroacetic acid) (C-10) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by addition of HATU (51.30 mg, 134.92 μmol). Then reaction mixture was stirred at 25 °C for 12 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to afford crude product. The crude product was purified by Prep-HPLC to afford a product 3-[4-[1-[6-[4-[5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2- carbonyl]piperazin-1-yl]-6-oxo-hexanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1- yl]piperidine-2,6-dione) (Compound 71) (29 mg, 23.30 μmol, 25.90% yield, 95.95% purity) as off-white solid. Prep. HPLC condition: Column/dimensions: X BRIDGE-C18 (19*250, 5 μm); Mobile phase A: 5 mM Ammonium acetate; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/40, 2/40, 10/60, 10.01/100, 12/100, 12.01/40, 15/40; Flow rate: 17 mL/min; Solubility: ACN+water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1194.57 [M+H]⁺; Retention time (min): 1.53; ¹H NMR (400 MHz, DMSO-d6): δ 11.10 (bs, 1H), 9.13 (s, 1H), 8.21 (s, 1H), 7.77–7.73 (m, 1H), 7.36–7.32 (m, 2H), 7.01–6.97 (m, 4H), 5.38–5.19 (m, 2H), 5.06 (q, J = 11.2, 5.6 Hz, 2H), 4.58 (d, J = 7.2 Hz, 1H), 4.31 (s, 2H), 4.17–3.94 (m, 3H), 3.79– 3.48 (m, 10H), 3.18–2.74 (m, 8H), 2.72–2.56 (m, 3H), 2.34 (s, 4H), 2.22–1.93 (m, 7H), 1.89– 1.17 (m, 11H), 1.52 (bs, 4H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 72: Synthesis of 3-[4-[1-[10-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]- 10-oxo-decanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 72): To a stirred solution of of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (0.07 g, 89.94 μmol, hydrochloric acid) (A-5) and 10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-4-yl]-1-piperidyl]-10-oxo-decanoic acid (40.34 mg, 62.96 μmol, trifluoroacetic acid) (C-11) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by addition of HATU (51.30 mg, 134.92 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) to afford solid precipitated. The precipitated solid was filtered to afford crude product which was purified by Prep-HPLC to afford 3-[4-[1-[10-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-10-oxo-decanoyl]-4- piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 72) (18 mg, 13.24 μmol, 14.72% yield, 95.35% purity, formic acid) as an off-white solid. Prep. HPLC condition: Column/dimensions: X-SELECT C18 (150*19*5 μ); Mobile phase A: 0.1% Formic acid in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/20, 2/20, 8/47, 12/47, 12.01/95, 14/95; Flow rate: 18 mL/min; Solubility: ACN+water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1250.68[M+H]⁺; Retention time (min): 1.67; ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (bs, 1H), 9.13 (s, 1H), 8.21 (s, 1H), 7.77–7.73 (q, J = 9.2, 6.0 Hz, 1H), 7.36–7.31 (m, 2H), 7.02–6.94 (m, 4H), 5.40–5.21 (m, 2H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.56 (d, J = 6.8 Hz, 1H), 4.33 (s, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.93 (d, J = 8.4 Hz, 1H), 3.81–2.63 (m, 4H), 3.59 (s, 3H), 3.46–3.43 (m, 5H), 3.16–2.90 (m, 5H), 2.87–2.52 (m, 6H), 2.32 (bs, 6H), 2.21–1.92 (m, 7H), 1.78–1.68 (m, 5H), 1.62 (bs, 1H), 1.52 (bs, 5H), 1.34–1.20 (bs, 8H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 73: Synthesis of 3-[4-[1-[12-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]- 12-oxo-dodecanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 73): O O N _N N N N 9 O F N N O Et N N N O NH N O N O F OH F Compound 73 To a stirred solution of of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro h h d li i l h ido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (0.07 g, 89.94 μmol, hydrochloric acid) (A-5) and 12-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-4-yl]-1-piperidyl]-12-oxo-dodecanoic acid (42.10 mg, 62.96 μmol, trifluoroacetic acid) (C-12) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by addition of HATU (51.30 mg, 134.92 μmol) . Then reaction mixture was stirred at 25 °C for 12 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to afford crude product. The crude product was purified by Prep-HPLC to afford a product3-[4-[1-[12-[4-[5-[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2- carbonyl]piperazin-1-yl]-12-oxo-dodecanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1- yl]piperidine-2,6-dione (Compound 73) (26 mg, 20.25 μmol, 22.51% yield, 99.56% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X BRIDGE-C18 (19*250, 5 μm); Mobile phase A: 5 mM Ammonium acetate; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/40, 2/40, 10/60, 10.01/100, 12/100, 12.01/40, 15/40; Flow rate: 17 mL/min; Solubility: ACN+water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1278.65 [M+H]⁺; Retention time (min): 1.76; ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (bs, 1H), 9.13 (s, 1H), 8.21 (s, 1H), 7.77–7.73 (q, J = 9.2, 6.0 Hz, 1H), 7.36–7.31 (m, 2H), 7.02–6.94 (m, 4H), 5.40–5.21 (m, 2H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.56 (d, J = 6.8 Hz, 1H), 4.33 (s, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.93 (d, J = 8.4 Hz, 1H), 3.81–3.44 (m, 12H), 3.16–2.80 (m, 8H), 2.73–2.52 (m, 3H), 2.32 (bs, 3H), 2.21–1.92 (m, 7H), 1.78–1.68 (m, 7H), 1.52 (bs, 7H), 1.34–1.20 (bs, 12H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 74: Synthesis of N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-5-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-

4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-5-oxo-pentanamide (Compound 74): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (A-5) (0.07 g, 89.94 μmol, hydrochloric acid) and 5-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methylamino]-5-oxo-pentanoic acid (C-13) (33.84 mg, 62.96 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by HATU (51.30 mg, 134.92 μmol). The reaction mixture was stirred at 25 °C for 12 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtain crude product. The crude product was purified by Prep-HPLC to afford product as off white solid. Product purity was not passed, 18 mg was submitted for achiral SFC purification. The compound was purified by achiral SFC to afford N- [[1-(2,6-dioxo-3-pi id l) 2 b [ d]i d l 6 l] h l] 5 [4 [5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2- carbonyl]piperazin-1-yl]-5-oxo-pentanamide (Compound 74) (12 mg, 9.99 μmol, 11.10% yield, 95.46% purity) as off-white solid. Prep-HPLC condition: Column/dimensions: X-SELECT C18 (19*250) 5μ; Mobile phase A: 0.1% FA in water; Mobile phase B: CAN; Gradient (Time/%B): 0/20, 3/20, 7.0/40, 14.0/30, 14.10/98,1 6.0/98; Flow rate: 17 mL/min; Solubility: THF+ACN+Water; SFC-Prep condition: Column Name: Ethyl Pyridine (30x250) mm, 5μ; Mobile Phase-A: CO₂; Mobile Phase-B :( 0.1% 7N Methanolic ammonia in ACN: methanol (1:1); Gradient program (T/%B): 100; Flow Rate (mL/minute): 35; Sample Loading (mg/Injection): 0.0045; No. of Injection’s: 04; Spot visualization: UV active compound; LCMS [ES⁺]: 1147.63 [M+H]⁺; Retention time (min): 2.04; ¹H NMR (400 MHz, DMSO-d6): δ 9.13– 8.95 (bs, 2H), 8.37–8.34 (m, 2H), 8.21 (s, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.77–7.72 (m, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.37–7.30 (m, 2H), 7.08 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 5.47 (d, J = 6.8 Hz, 1H), 5.38–5.21 (m, 1H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.67 (d, J = 6.4 Hz, 2H), 4.33 (s, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.80–3.64 (m, 4H), 3.54 (bs, 4H), 3.18–2.89 (m, 6H), 2.88–2.69 (m, 2H), 2.54 (bs, 2H), 2.39–2.28 (m, 3H), 2.18–1.96 (m, 7H), 1.92 (s, 2H), 1.89–1.73 (m, 5H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 75: Synthesis of N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-7-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-7-oxo-heptanamide (Compound 75):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (0.07 g, 89.94 μmol, hydrochloric acid) (0.07 g, 89.94 μmol, hydrochloric acid) (A-5) and 7-[[1-(2,6-dioxo-3- piperidyl)-2-oxo-benzo[cd]indol-6-yl]methylamino]-7-oxo-heptanoic acid (C-14) (35.60 mg, 62.96 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by HATU (51.30 mg, 134.92 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, ice-cold water (10 mL) was added to the reaction mixture to afford solid. A solid was filtered to afford crude product which was purified by prep-HPLC to afford N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]-7-[4-[5-[7-(8-ethyl-7-fluoro- 3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2- carbonyl]piperazin-1-yl]-7-oxo-heptanamide (Compound 75) (11 mg, 8.56 μmol, 9.51% yield, 95.01% purity, formic acid)as off-white solid. Prep-HPLC condition: Column/dimensions: X- SELECT C18 (150*19*5 μ); Mobile phase A: 0.1% Formic acid in water (aq); Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/20,3/30,7//42,13.10/42, 14/95, 14/95; Flow rate: 17 mL/min; Solubility: ACN+THF+water; Spot visualization: UV active compound; LCMS [ES⁺]: 1175.75 [M+H]⁺; Retention time (min): 5.57; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (bs, 1H), 9.96 (bs, 1H), 9.13 (s, 1H), 8.21 (s, 1H), 7.77–7.74 (q, J = 8.8, 6.4 Hz, 1H), 7.36–7.32 (m, 2H), 7.01 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.60 (d, J = 8.0 Hz, 2H), 5.67 (d, J = 7.6 Hz, 1H), 5.40– 5.21 (m, 2H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.55 (d, J = 6.8 Hz, 1H), 4.33 (s, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.93 (d, J = 8.4 Hz, 1H), 3.81–3.62 (m, 4H), 3.54 (s, 4H), 3.16–2.90 (m, 6H), 2.86–2.54 (m, 4H), 2.32 (s, 5H), 2.19–1.96 (m, 7H), 1.88–1.67 (m, 8H), 1.52 (bs, 5H), 1.33 (bs, 3H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 76: Synthesis of N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-10-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-10-oxo-decanamide (Compound 76): To a stirred solution [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-2-yl]-piperazin-1-yl-methanone (A-5) (0.07 g, 89.94 μmol, hydrochloric acid) and 10-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methylamino]-10-oxo-decanoic acid (C-15) (38.25 mg, 62.96 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by HATU (51.30 mg, 134.92 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtain crude product. The crude product was purified by Prep-HPLC to afford N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]-10-[4- [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[4,3-c]azepine-2-carbonyl]piperazin-1-yl]-10-oxo-decanamide (Compound 76) (19 mg, 14.77 μmol, 16.42% yield, 98.22% purity, Formic acid) as off-white solid. Prep- HPLC condition: Column Name: C18; 250 x 20mm; 5μm; Mobile Phase-A: 0.10 % Formic acid in water; Mobile Phase-B: Acetonitrile; Gradient program: (T/%B) 0/30, 2/30, 12/50, 13/50, 13.1/98, 16/98, 16.1/30, 19/30; Flow Rate (mL/minute):18; Solubility: THF+ACN+Water; Spot visualization: UV active compound; LCMS [ES⁺]: 1217.72 [M+H]⁺; Retention time (min): 1.66; ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (bs, 1H), 9.13 (s, 1H), 8.36–8.32 (m, 2H), 8.22 (s, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.77–7.73 (m, 1H), 7.43–7.31 (m, 3H), 7.09 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 5.47 (d, J = 6.8 Hz, 1H), 5.38–5.21 (m, 1H), 5.12–4.98 (q, J = 10.6, 5.6 Hz, 2H), 4.67 (d, J = 6.4 Hz, 1H), 4.33 (s, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.80–3.64 (m, 4H), 3.54 (bs, 2H), 3.18–2.89 (m, 7H), 2.88–2.69 (m, 2H), 2.54 (bs, 4H), 2.32 (bs, 3H), 2.18–1.96 (m, 9H), 1.89–1.73 (m, 3H), 1.48 (bs, 4H), 1.19 (bs, 8H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 77: Synthesis of 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-

d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 77): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (0.07 g, 89.94 μmol, hydrochloric acid) and 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]acetic acid (C-17) (28.93 mg, 62.96 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (34.87 mg, 269.83 μmol, 47.00 μL) followed by HATU (51.30 mg, 134.92 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. After completion, ice-cold water (5 mL) was added to the reaction mixture and lyophilized to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 77) (26 mg, 22.87 μmol, 25.43% yield, 98.11% purity, formic acid) as an off-white solid. Column Name: C18; 250 x 20 mm; 5 μm; Mobile Phase-A: 0.10 % Formic acid in water; Mobile Phase-B: Acetonit il G di t (T/%B) 0/30 2/30 12/50, 13/50, 13.1/98, 16/98, 16.1/30, 19/30; Flow Rate (mL/minute):18; Solubility: THF+ACN+WATER; LCMS [ES⁺]: 1069.64 [M+H]⁺; Retention time (min): 1.29; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 9.19 (s, 1H), 8.39 (bs, 2H), 7.78–7.73 (m, 1H), 7.37–7.29 (m, 2H), 7.04–6.88 (m, 3H), 6.67– 6.54 (m, 3H), 5.64 (d, J = 7.2 Hz, 1H), 5.36–5.14 (m, 3H), 4.58–4.47 (m, 2H), 4.42–4.21 (m, 3H) ,4.16–3.92 (m, 4H), 3.63 (bs, 6H), 3.16 (bs, 2H), 3.12–2.55 (m, 8H), 2.41–2.26 (m, 4H), 2.16–1.94 (m, 7H), 1.91–1.72 (m, 4H), 1.70–1.63 (m, 2H), 1.66 (bs, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 78: Synthesis of 3-[4-[1-[4-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-4-oxo-butanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 78): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (70 mg, 89.94 μmol, hydrochloric acid) and 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]-4-oxo-butanoic acid (C-1) (29.32 mg, 58.46 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by HATU (51.30 mg, 134.92 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, ice-cold water (5 mL) was added to the reaction mixture to afford solid. A solid was filtered to afford crude product which was purified by prep-HPLC to afford 3-[4-[1-[4-[4-[5-[7-(8-ethyl-7-fluoro- 3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]-4-oxo-butanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 78) (12 mg, 9.67 μmol, 10.75% yield, 93.21% purity, formic acid) as off-white solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18 (19*250, 5μm); Mobile phase A: 0.1% Formic acid in water; Mobile phase B: 100 % Acetonitrile; Gradient (Time/%B): 0/10, 2/10, 10/52 15/52 16/100 18/100 19/10; Flow rate: 17 mL/min; Solubility: ACN+Water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: 1111.67 [M+H]⁺; Retention time (min): 1.49; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 10.02 (bs, 1H), 9.22 (s, 1H), 8.46 (bs, 1H), 7.77–7.74 (m, 1H), 7.36–7.32 (m, 2H), 7.01 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.65 (s, 1H), 6.60 (d, J = 8.4 Hz, 2H), 5.67 (d, J = 7.2 Hz, 1H), 5.38–5.19 (m, 3H), 4.56–4.48 (m, 3H), 4.42–4.22 (m, 3H), 4.19–3.89 (m, 5H), 3.64–3.47 (m, 6H), 3.16–2.97 (m, 4H), 2.87–2.63 (m, 2H), 2.56 (bs, 6H), 2.35 (bs, 2H), 2.17–1.94 (m, 5H), 1.81–1.66 (m, 7H), 1.52 (bs, 1H), 1.35 (bs, 1H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 79: Synthesis of 3-[4-[1-[7-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-7-oxo-heptanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 79):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (70 mg, 89.94 μmol, hydrochloric acid) and 7-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]-7-oxo-heptanoic acid (C-2) (31.78 mg, 58.46 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (11.62 mg, 89.94 μmol, 15.67 μL) followed by HATU (34.20 mg, 89.94 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, ice-cold water (5 mL) was added to the reaction mixture to afford solid. A solid was filtered to afford crude product which was purified by prep-HPLC to afford 3-[4-[1-[7-[4-[5-[7-(8-ethyl-7-fluoro- 3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]-7-oxo-heptanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 79) (18 mg, 14.69 μmol, 16.34% yield, 97.91% purity, Formic acid) as off-white solid. Prep. HPLC condition: Column/dimensions: X-BRIDGE C18 (19*250, 5μm); Mobile phase A: 0.1% Formic acid in water; Mobile phase B: 100 % Acetonitrile; Gradient (Time/%B): 0/10, 2/10, 10/52 15/52 16/100 18/100 19/10; Flow rate: 17 mL/min; Solubility: ACN+Water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: 1154.70 [M+H]⁺; Retention time (min): 1.52; ¹H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 9.18 (s, 1H), 8.47 (bs, 1H), 7.77–7.74 (q, J = 13.2, 6.0 Hz, 1H), 7.36–7.32 (m, 2H), 7.09 (s, 1H), 6.94 (d, J = 8.0 Hz, 2H), 6.65 (s, 1H), 6.60 (d, J = 8.4 Hz, 2H), 5.67 (d, J = 7.2 Hz, 1H), 5.38–5.19 (m, 3H), 4.56–4.48 (m, 3H), 4.41–4.22 (m, 3H), 4.18–3.86 (m, 5H), 3.64–3.44 (m, 7H), 3.14–2.93 (m, 4H), 2.88–2.54 (m, 4H), 2.35 (bs, 6H), 2.17–1.96 (m, 5H), 1.89–1.69 (m, 7H), 1.57–1.42 (bs, 5H), 1.27 (s, 3H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 80: Synthesis of 3-[4-[1-[10-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S) fl h h d li i l ethoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-10-oxo-decanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 80): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (60 mg, 77.09 μmol, hydrochloric acid) and 10-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]-10-oxo-decanoic acid (C-3) (31.60 mg, 53.97 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (24.91 mg, 192.74 μmol, 33.57 μL) followed by HATU (43.97 mg, 115.64 μmol). The reaction mixture was stirred at 25 °C for 16 hours. Reaction was monitored by TLC and LCMS. After completion, ice-cold water (5ml) was added to the reaction mixture to afford solid, which was filtered to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[4-[1-[10-[4-[5-[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]-10-oxo-decanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 80) (26 mg, 21.38 μmol, 27.74% yield, 98.31% purity) as an off-white solid. Prep. HPLC condition: Column/dimensions: X SELECT C18 (19*250, 5μm); Mobile phase A: 10 mM Ammonium acetate in water; Mobile phase B: 100 % Acetonitrile; Gradient (Time/%B): 0/35, 2/35, 10/65, 10.5/65, 13/10015/35; Flow rate: 18 mL/min; Solubility: ACN+Water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: 1195.75 [M+H]⁺; Retention time (min): 1.62; ¹H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 10.36 (bs, 1H), 9.18 (s, 1H), 7.77–7.74 (m, 1H), 7.36–7.32 (m, 2H), 7.10 (s, 1H), 7.01–6.93 (m, 2H), 6.65 (s, 1H), 6.60 (d, J = 8.4 Hz, 2H), 5.67 (d, J = 7.2 Hz, 1H), 5.38–5.19 (m, 3H), 4.62–4.48 (m, 3H), 4.41–4.22 (m, 3H), 4.18–3.86 (m, 5H), 3.64–3.44 (m, 6H), 3.14–2.93 (m, 4H), 2.88–2.54 (m, 3H), 2.35 (bs, 6H), 2.17–1.93 (m, 5H), 1.89–1.69 (m, 7H), 1.63–1.39 (bs, 8H), 1.27 (s, 8H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 81: Synthesis of 3-[4-[1-[12-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-12-oxo-dodecanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 81): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (60 mg, 77.09 μmol, hydrochloric acid) and 12-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]-12-oxo-dodecanoic acid (C-4) (33.12 mg, 53.97 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (24.91 mg, 192.74 μmol, 33.57 μL) followed by HATU (43.97 mg, 115.64 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, ice-cold water (5 mL) was added to the reaction mixture to afford solid. A solid was filtered to afford crude product which was purified by prep-HPLC to afford 3-[4-[1-[12-[4-[5-[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]-12-oxo-dodecanoyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 81) (26 mg, 20.29 μmol, 26.32% yield, 99.08% purity, Formic acid) as an off-white solid. Prep. HPLC condition: Column/dimensions: X SELECT C18 (19*250, 5μm); Mobile phase A: 0.1% Formic acid in water; Mobile phase B: 100 % Acetonitrile; Gradient (Time/%B): 0/30, 3/30, 7/45, 16/30, 12/45, 12.10/98, 14.1/30; Flow rate: 17 mL/min; Solubility: ACN+Water+THF ; Spot visualization: UV active compound; LCMS [ES⁺]: 1223.77 [M+H]⁺; Retention time (min): 1.72; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 10.13 (bs, 1H), 9.18 (s, 1H), 8.45 (s, 1H), 7.77–7.74 (m, 1H), 7.36–7.32 (m, 2H), 7.10 (s, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.65 (s, 1H), 6.60 (d, J = 8.4 Hz, 2H), 5.67 (d, J = 7.2 Hz, 1H), 5.38–5.19 (m, 3H), 4.59–4.48 (m, 3H), 4.41–4.22 (m, 3H), 4.18–3.86 (m, 5H), 3.64–3.44 (m, 6H), 3.14–2.93 (m, 4H), 2.88–2.54 (m, 6H), 2.35 (bs, 6H), 2.17–1.93 (m, 5H), 1.89–1.69 (m, 6H), 1.57–1.39 (bs, 5H), 1.27 (s, 12H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 82: Synthesis of 3-[5-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 82):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (70 mg, 89.94 μmol, hydrochloric acid) (A-6) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]acetic acid (30.08 mg, 58.46 μmol, trifluoroacetic acid) (C-21) in N,N-dimethylformamide (1.5 mL) at 0 °C was DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by HATU (51.30 mg, 134.92 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was monitored by TLC and LCMS. To the crude product water was added water (5ml) to afford solid. A solid was filtered to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[5-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1- yl]piperidine-2,6-dione (Compound 82) (12 mg, 10.18 μmol, 11.32% yield, 95.40% purity) as an off-white solid. Prep-HPLC condition: Column/ dimensions: X BRIDGE C18 (19*250, 5μm); Mobile phase A: 5 mM Ammonium acetate in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/18, 2/18, 10/36, 16/36, 16.01/98; Flow rate: 18 mL/min; Solubility: THF+ACN+Water; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1124.68 [M+H]⁺; Retention time (min): 4.44; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.19 (s, 1H), 7.77–7.74 (m, 1H), 7.36–7.32 (m, 2H), 7.10 (s, 1H), 7.01–6.99 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 5.36–5.17 (m, 4H), 4.62–4.48 (m, 2H), 4.41–4.22 (m, 2H), 4.18–3.89 (m, 4H), 3.68–3.44 (m, 7H), 3.25 (bs, 3H), 3.14–2.88 (m, 8H), 2.76–2.54 (m, 4H), 2.33 (bs, 2H), 2.17–1.93 (m, 5H), 1.89–1.69 (m, 10H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 83: Synthesis of 3-[5-[1-[4-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S) 2 fl 123567 h h d li i 8 l] ethoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-4-oxo-butanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 83): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (0.07 g, 89.94 μmol, hydrochloric acid) and 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-4-oxo-butanoic acid (C-5) (35.04 mg, 62.96 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.46 mL) at 0 °C was added HATU (51.30 mg, 134.92 μmol) followed by DIPEA (34.87 mg, 269.83 μmol, 47.00 μL). The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. After completion, ice-cold water (5 mL) was added to the reaction mixture and lyophilized to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[5-[1-[4-[4-[5-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-4-oxo-butanoyl]-4- piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 83) (15 mg, 11.76 μmol, 13.07% yield, 95.04% purity, formic acid) as an off-white solid. Column Name: C18; 250 x 20 mm; 5μm; Mobile Phase-A: 0.10 % Formic acid in Water; Mobile Phase-B: Acetonitrile; Gradient program: (T/%B) 0/30, 2/30, 12/50, 13/50, 13.1/98, 16/98, 16.1/30, 19/30; Flow Rate (mL/minute):18; Solubility: THF+ACN+Water; LCMS [ES⁺]: 1166.67 [M+H]⁺; Retention time (min): 5.28; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.19 (s, 1H), 7.77– 7.74 (m, 1H), 7.36–7.32 (m, 2H), 7.10 (s, 1H), 7.01–6.99 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.66 (s, 1H), 5.36–5.19 (m, 4H), 4.62–4.48 (m, 3H), 4.41–4.22 (m, 2H), 4.18–3.86 (m, 5H), 3.64– 3.44 (m, 5H), 3.34 (bs, 4H), 3.14–2.93 (m, 4H), 2.89–2.76 (m, 4H), 2.68–2.54 (m, 7H), 2.35 (bs, 2H), 2.17–1.93 (m, 6H), 1.89–1.69 (m, 5H), 1.65 (bs, 1H), 1.48 (bs, 1H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 84: Synthesis of 3-[5-[1-[6-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-6-oxo-hexanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 84):

To a stirred solution of To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl- methanone (A-6) (60 mg, 77.09 μmol, hydrochloric acid) and 6-[4-[1-(2,6-dioxo-3-piperidyl)- 3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-6-oxo-hexanoic acid (31.55 mg, 53.97 μmol, trifluoroacetic acid) (C-6) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (24.91 mg, 192.74 μmol, 33.57 μL) followed by HATU (43.97 mg, 115.64 μmol). The reaction mixture was stirred at 25 °C for 16 hours. Reaction was monitored by TLC and LCMS. After completion, ice-cold water (5ml) was added to the reaction mixture to afford solid. The crude product was purified by Prep-HPLC to obtain 3-[5-[1-[6-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]- 6-oxo-hexanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 84) (17 mg, 13.53 μmol, 17.55% yield, 98.7% purity, Formic acid) as an off-white solid. Prep. HPLC condition: Column/dimensions: X SELECT C18 (19*250, 5μm); Mobile phase A: 0.1% Formic acid in water; Mobile phase B: 100 % Acetonitrile; Gradient (Time/%B): 0/25, 3/25, 7/32, 13.20/32, 13.21/98, 16.20/98, 16.21/25; Flow rate: 17 mL/min; Solubility: ACN+Water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: 1049.64 [M+H]⁺; Retention time (min): 1.23; ¹H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 9.18 (s, 1H), 8.43 (s, 2H), 7.77–7.74 (m, 1H), 7.36–7.32 (m, 2H), 7.10 (s, 1H), 7.01–6.99 (m, 2H), 6.91 (d, J = 7.6 Hz, 1H), 6.65 (s, 1H), 5.36–5.17 (m, 4H), 4.62–4.48 (m, 3H), 4.41–4.22 (m, 2H), 4.18–3.86 (m, 5H), 3.64–3.44 (m, 5H), 3.14–2.93 (m, 4H), 2.89–2.54 (m, 5H), 2.35 (bs, 8H), 2.17–1.93 (m, 5H), 1.89–1.69 (m, 6H), 1.63–1.39 (bs, 8H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 85: Synthesis of 3-[5-[1-[10-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-10-oxo-decanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6- dione (Compound 85): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (50 mg, 64.25 μmol, hydrochloric acid) and 10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-10-oxo-decanoic acid (28.81 mg, 44.97 μmol, trifluoroacetic acid) (C-7) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (20.76 mg, 160.61 μmol, 27.98 μL) followed by HATU (36.64 mg, 96.37 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was monitored by TLC and LCMS. To the crude product water was added water (5ml) to afford solid. A solid was filtered to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[5-[1-[10-[4-[5-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-10-oxo-decanoyl]-4- piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (14 mg, 10.36 μmol, 16.13% yield, 95.96% purity, Formic acid) (Compound 85) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-SELECT- C18; Mobile phase A: 0.1% Formic acid in water; Mobile phase B: ACN; Gradient (Time/%B): 0/30, 2/30, 9/41, 13/41, 15/100, 15/100, 15.1/30, 18/30; Flow rate: 18mL/min; Solubility: H2O+ACN+THF; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1248.66 [M+H]⁺; Retention time (min): 1.62; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.18 (s, 1H), 7.77–7.74 (m, 1H), 7.36–7.32 (m, 2H), 7.10 (s, 1H), 7.01–6.99 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 5.36–5.17 (m, 4H), 4.62–4.48 (m, 3H), 4.41–4.22 (m, 2H), 4.18–3.86 (m, 6H), 3.64–3.44 (m, 8H), 3.14–2.93 (m, 6H), 2.89–2.54 (m, 6H), 2.35 (bs, 4H), 2.17–1.93 (m, 4H), 1.89–1.69 (m, 6H), 1.63–1.39 (bs, 8H), 1.27 (s, 8H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 86: Synthesis of 3-[5-[1-[12-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-12-oxo-dodecanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6- dione (Compound 86):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (70 mg, 89.94 μmol, hydrochloric acid) (A-6) and 12-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]-12-oxo-dodecanoic acid (39.09 mg, 58.46 μmol, trifluoroacetic acid) (C-8) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by HATU (51.30 mg, 134.92 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was monitored by TLC and LCMS. To the crude product water was added water (5ml) to afford solid. A solid was filtered to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[5-[1-[12-[4-[5-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-12-oxo-dodecanoyl]-4- piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 86) (17 mg, 12.60 μmol, 14.01% yield, 98.19% purity, Formic acid) as an off-white solid. Prep-HPLC condition: Column/ dimensions: Sunfire C18 (19*150, 5μm; Mobile phase A: 0.1% Formic acid in water; Mobile phase B: Acetonitrile; Gradient (Time/%B):0/20, 2/20, 8/42, 12/42, 12.01/100, 15.01/20; Flow rate: 18 mL/min; Solubility: THF+ACN+Water; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1278.88 [M+H]⁺; Retention time (min): 1.70; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.18 (s, 1H), 8.46 (s, 1H) 7.77–7.74 (m, 1H), 7.36–7.32 (m, 2H), 7.10 (s, 1H), 7.01–6.99 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 5.36–5.17 (m, 4H), 4.62– 4.48 (m, 3H), 4.41–4.22 (m, 2H), 4.18–3.86 (m, 4H), 3.64–3.44 (m, 7H), 3.25 (bs, 3H), 3.14– 2.98 (m, 4H), 2.89–.54 (m, 6H), 2.33 (bs, 7H), 2.17–1.93 (m, 5H), 1.89–1.69 (m, 5H), 1.63–1.39 (bs, 6H), 1.23 (s, 12H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 87: Synthesis of 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 87): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (0.07 g, 89.94 μmol, hydrochloric acid) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-4-yl]-1-piperidyl]acetic acid (C-22) (32.39 mg, 62.96 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.46 mL) at 0 °C was added HATU (51.30 mg, 134.92 μmol) followed by DIPEA (34.87 mg, 269.83 μmol, 47.00 μL). The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. After completion, ice-cold water (5 mL) was added to the reaction mixture and lyophilized to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[43-d]pyrimidin-4-yl]-4678-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1- yl]piperidine-2,6-dione (Compound 87) (22 mg, 17.87 μmol, 19.87% yield, 95.07% purity, formic acid) as an off-white solid. Column Name: C18; 250 x 20 mm; 5μm; Mobile Phase-A: 0.10 % Formic acid in water; Mobile Phase-B: Acetonitrile; Gradient program: (T/%B) 0/30, 2/30, 12/50, 13/50, 13.1/98, 16/98, 16.1/30, 19/30; Flow Rate (mL/minute):18; Solubility: THF+ACN+Water; LCMS [ES⁺]: 1124.76 [M+H]⁺; Retention time (min): 5.38; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 10.52–9.64 (bs, 1H), 9.19 (s, 1H), 7.78–7.73 (m, 1H), 7.37– 7.31 (m, 2H), 7.04–6.92 (m, 4H), 6.66 (s, 1H), 5.42–5.15 (m, 4H), 4.53 (bs, 2H), 4.42–4.36 (m, 2H), 4.16–3.92 (m, 4H), 3.68–3.52 (m, 8H), 3.22–2.17 (m, 13H), 2.35 (bs, 2H), 2.23–1.93 (m, 8H), 1.88–1.67 (m, 7H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 88: Synthesis of 3-(4-(1-(4-(4-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carbonyl)piperazin-1-yl)-4-oxobutanoyl)piperidin-4-yl)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound 88):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (0.07 g, 89.94 μmol, hydrochloric acid) and 4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-4-yl]-1-piperidyl]-4-oxo-butanoic acid (C-9) (27.86 mg, 47.01 μmol, trifluoromethanesulfonic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (34.87 mg, 269.83 μmol, 47.00 μL) followed by HATU (51.30 mg, 134.92 μmol) portion wise at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours while monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) to afford precipitate. The precipitated solid was filtered to afford crude product. The crude product was purified by prep-HPLC to obtain 3-[4-[1-[4-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]- 4-oxo-butanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 88) (13 mg, 10.85 μmol, 12.06% yield, 97.30% purity) as an off-white solid. Prep- HPLC condition: Column/dimensions: X-SELECT; Mobile phase A: 5mM Ammonium acetate in water; Mobile phase B: ACN; Gradient (Time/%B): 0/20, 2/20, 8/40, 20/40, 20.01/100, 23/100,23.1/20, 26/20; Flow rate: 18 mL/min; Solubility: H2O+CAN; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1166.68 [M+H]⁺; Retention time (min): 1.47; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 9.18 (s, 1H), 7.77–7.73 (m, 1H), 7.36–7.32 (m, 2H), 7.01– 6.97 (m, 4H), 6.66 (s, 1H), 5.38–5.19 (m, 4H), 4.59–4.48 (m, 3H), 4.41–4.22 (m, 2H), 4.18–3.86 (m, 5H), 3.64–3.44 (m, 9H), 3.14–2.93 (m, 4H), 2.88–2.54 (m, 8H), 2.35 (bs, 2H), 2.17–1.93 (m, 6H), 1.89–1.69 (m, 8H), 1.57–1.39 (bs, 2H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 89: Synthesis of 3-[4-[1-[6-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-6-oxo-hexanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 89): To a stirred solution of 6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]-1-piperidyl]-6-oxo-hexanoic acid (C-10) (27.51 mg, 47.06 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1.5 mL) was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) and HATU (51.30 mg, 134.92 μmol) at 0 °C. Reaction mixture was stirred at 0 °C for 5 minutes and [5-[7- (8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (70 mg, 89.94 μmol, hydrochloric acid) was added to the reaction mixture at the same temperature. The reaction mixture was stirred at room temperature for 16 hours while monitored by TLC and LCMS. After completion the reaction mixture was diluted with water (5 mL) and acetonitrile (0.5 mL). The reaction mixture was lyophilized to obtain crude product. The crude product was purified by Prep-HPLC to obtain 3-[4-[1-[6-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-6-oxo- hexanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 89) (11 mg, 8.46 μmol, 9.40% yield, 95.34% purity, Formic acid) as an off-white solid. Prep HPLC condition: Column/dimensions: Sunfire-C18 (150*19*5 μ); Mobile phase A: 0.1% Formic acid in water; Mobile phase B: ACN; Gradient (Time/%B): 0/15, 2/15, 8/30, 13/30, 13.01/100,15.01/15; Flow rate: 18 mL/min; Solubility: H₂O+ACN+THF; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1194.67 [M+H]⁺; Retention time (min): 4.39; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 10.13 (bs, 1H), 9.19 (s, 1H), 7.77–7.73 (m, 1H), 7.36– 7.32 (m, 2H), 7.01–6.97 (m, 4H), 6.65 (s, 1H), 5.38–5.19 (m, 4H), 4.59–4.48 (m, 3H), 4.41–4.22 (m, 2H), 4.18–3.89 (m, 5H), 3.64–3.44 (m, 10H), 3.14–2.96 (m, 5H), 2.92–2.54 (m, 4H), 2.35 (bs, 6H), 2.17–1.93 (m, 5H), 1.89–1.69 (m, 5H), 1.57–1.39 (bs, 7H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 90: Synthesis of 3-[4-[1-[10-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-10-oxo-decanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6- dione (Compound 90):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (50 mg, 64.25 μmol, hydrochloric acid) and 10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-4-yl]-1-piperidyl]-10-oxo-decanoic acid (28.81 mg, 44.97 μmol, trifluoroacetic acid) (C-11) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (8.30 mg, 64.25 μmol, 11.19 μL) followed by HATU (24.43 mg, 64.25 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was monitored by TLC and LCMS. To the crude product, water (5 mL) was added to afford solid. A solid was filtered to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[4-[1-[10-[4-[5-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-10-oxo-decanoyl]-4- piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (14 mg, 10.68 μmol, 16.62% yield, 98.88% purity, formic acid) (Compound 90) as an off-white solid. Prep HPLC condition: Column/dimensions: X-SELECT- C18; Mobile phase A: 0.1% Formic acid in water; Mobile phase B: ACN; Gradient (Time/%B): 0/30, 2/30, 12/45, 13/45, 13.1/98, 16/98, 16.1/30, 19/30; Flow rate: 18 mL/min; Solubility: H2O+ACN+THF; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1250.79 [M+H]⁺; Retention time (min): 1.61; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 10.13 (bs, 1H), 9.18 (s, 1H), 7.77–7.73 (m, 1H), 7.36 –7.32 (m, 2H), 7.01–6.97 (m, 4H), 6.65 (s, 1H), 5.38–5.19 (m, 4H), 4.59–4.48 (m, 3H), 4.41–4.22 (m, 2H), 4.18–3.86 (m, 5H), 3.64–3.44 (m, 8H), 3.14–2.93 (m, 5H), 2.88–2.54 (m, 5H), 2.35 (bs, 4H), 2.17–1.93 (m, 6H), 1.89–1.69 (m, 7H), 1.57–1.39 (bs, 7H), 1.27 (s, 8H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 91: Synthesis of 3-[4-[1-[12-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S) 2 fl 123567 h h d li i 8 l] ethoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-12-oxo-dodecanoyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6- dione (Compound 91): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (60 mg, 77.09 μmol, hydrochloric acid) and 12-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-4-yl]-1-piperidyl]-12-oxo-dodecanoic acid (C-12) (36.09 mg, 53.97 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (24.91 mg, 192.74 μmol, 33.57 μL) followed by HATU (43.97 mg, 115.64 μmol). The reaction mixture was stirred at 25 °C for 16 hours while monitored by TLC and LCMS. After completion, ice-cold water (5 mL) was added to the reaction mixture to afford solid, which was filtered to afford crude product. The crude product was purified by Prep-HPLC to obtain 3-[4-[1-[12-[4-[5-[7-(8-ethyl- 7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[15-a][14]diazepine-2-carbonyl]piperazin-1-yl]-12-oxo-dodecanoyl]-4- piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 91) (33 mg, 24.72 μmol, 32.06% yield, 95.75% purity) as a pale pink solid. Prep. HPLC condition: Column/dimensions: X bridge C18 (30*150*5μm); Mobile phase A: 10 mM Ammonium acetate in water; Mobile phase B: 100 % Acetonitrile; Gradient (Time/%B): 0/30, 2/30, 10/55, 12.50/55, 12.51/98, 15.50/98, 18/30; Flow rate: 17 mL/min; Solubility: ACN+Water+THF; Spot visualization: UV active compound; LCMS [ES⁺]: 1278.77 [M+H]⁺; Retention time (min): 1.68; ¹H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 10.13 (s, 1H), 9.18 (s, 1H), 7.77–7.73 (m, 1H), 7.36–7.32 (m, 2H), 7.01–6.97 (m, 4H), 6.65 (s, 1H), 5.38–5.19 (m, 4H), 4.59–4.48 (m, 3H), 4.41–4.22 (m, 2H), 4.18–3.86 (m, 5H), 3.64–3.44 (m, 6H), 3.14–2.93 (m, 4H), 2.88–2.54 (m, 6H), 2.35 (bs, 6H), 2.17–1.93 (m, 5H), 1.89–1.69 (m, 8H), 1.57–1.39 (bs, 7H), 1.27 (s, 12H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 92: Synthesis of N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-5-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-5-oxo- pentanamide (Compound 92):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (70 mg, 89.94 μmol, hydrochloric acid) and 5-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methylamino]-5-oxo-pentanoic acid (C-13) (33.84 mg, 62.96 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by HATU (51.30 mg, 134.92 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, ice-cold water (5 mL) was added to the reaction mixture to afford solid. A solid was filtered to afford crude product which was purified by prep-HPLC to afford N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo- benzo[cd]indol-6-yl]methyl]-5-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-5-oxo- pentanamide (Compound 92) (33 mg, 26.40 μmol, 29.36% yield, 95.47% purity, Formic acid) as a off-white solid. Prep. HPLC condition: Column/dimensions: X-SELECT C18 (150*19*5 μ); Mobile phase A: 0.1% Formic acid in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/20, 2/20, 8/47, 12/47, 12.01/95, 15.1/20; Flow rate: 18 mL/min; Solubility: ACN+THF+water; Spot visualization: UV active compound. LCMS [ES⁺]: m/z 1147.59 [M+H]⁺; Retention time (min): 1.45. ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 10.04 (bs, 1H), 9.19 (s, 1H), 8.40–8.35 (m, 3H), 8.21 (s, 1H), 7.84 (5, J = 6.0 Hz, 1H), 7.77–7.74 (m, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.32–7.29 (m, 2H), 7.10 (d, J = 7.2 Hz, 1H), 7.01 (s, 1H), 6.65 (s, 1H), 5.36–5.17 (m, 4H), 4.69 (d, J = 5.6 Hz, 2H), 4.54 (bs, 2H), 4.42–4.22 (m, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.92 (bs, 2H), 3.62–3.50 (bs, 6H), 3.16–2.88 (m, 6H), 2.76–2.56 (m, 2H), 2.32 (bs, 4H), 2.18–1.95 (m, 6H), 1.78–1.69 (m, 5H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 93: Synthesis of N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-7-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-7-oxo- heptanamide (Compound 93): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (0.07 g, 89.94 μmol, hydrochloric acid) and 7-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methylamino]-7-oxo-heptanoic acid (C-14) (35.60 mg, 62.96 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by HATU (51.30 mg, 134.92 μmol). Then reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was monitored by TLC and LCMS. To the crude product was lyophilized to afford crude product. The crude product was purified by Prep-HPLC to afford the product N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]-7-[4-[5- [7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-7-oxo-heptanamide (Compound 93) (24 mg, 20.17 μmol, 22.43% yield, 98.79% purity) as an off-white solid. Prep. HPLC condition: Column Name: C18; 250x20mm; 5u; Column No#: GVKBLR/PREP/063; Mobile Phase-A: 0.10 % Formic acid in Water; Mobile Phase-B: Acetonitrile; Gradient program (T/%B): 0/20, 2/20, 10/45, 14/49, 14.1/100, 17/100, 17.1/20, 20/20; Flow Rate (mL/minute): 18; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1175.60 [M+H]⁺; Retention time (min): 5.37; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 10.76–9.82 (bs, 1H), 9.18 (s, 1H), 8.36–8.31 (m, 2H), 8.10 (d, J = 7.2 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.75 (q, J = 6.0 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.36–7.29 (m, 2H), 7.09 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.65 (s, 1H), 5.46–5.41 (m, 1H), 5.36–5.14 (m, 3H), 4.67 (d, J = 5.6 Hz, 1H), 4.52 (d, J = 6.0 Hz, 1H), 4.41–4.26 (m, 2H), 4.15–3.99 (m, 4H), 3.64–3.44 (m, 12H), 3.04–2.89 (m, 4H), 2.84– 2.72 (m, 2H), 2.25 (bs, 2H), 2.14–1.93 (m, 7H), 1.86–1.74 (m, 3H), 1.54–1.39 (m, 4H), 1.23 (bs, 2H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 94: Synthesis of N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-10-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-

4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-10-oxo- decanamide (Compound 94): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (70 mg, 89.94 μmol, hydrochloric acid) and 10-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol- 6-yl]methylamino]-10-oxo-decanoic acid (C-15) (38.25 mg, 62.96 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at room temperature was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by the addition HATU (51.30 mg, 134.92 μmol). The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by LCMS. The reaction mixture was diluted with water (5 mL) and directly kept for lyophilization to afford crude material. The crude material was purified by prep-HPLC to afford product N-[[1-(2,6-dioxo-3-piperidyl)-2- oxo-benzo[cd]indol-6-yl]methyl]-10-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]- 10-oxo-decanamide (Compound 94) (16 mg, 13.09 μmol, 14.56% yield, 99.62% purity) as a white solid. Column/dimensions: X-SELECT C18(19*250) 5μ; Mobile phase A: 0.1% Formic acid in water; Mobile phase B: CAN; Gradient (Time/%B): 0/20, 3/20, 7.0/40, 14.0/30, 14.10/98, 16.0/98; Flow rate: 17 mL/min; Solubility: THF+ACN+Water; LCMS [ES⁺]: m/z 1217.68 [M+H]⁺; Retention time (min): 1.57; ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 9.92 (bs, 1H), 9.18 (s, 1H), 8.36–8.29 (m, 2H), 8.10 (d, J = 7.2 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.76 (q, J = 6.0 Hz, 1H), 7.41–7.33 (m, 3H), 7.09 (d, J = 7.2 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.65 (s, 1H), 5.47–5.41 (m, 1H), 5.36–5.16 (m, 3H), 4.67 (d, J = 5.6 Hz, 2H), 4.52 (d, J = 5.6 Hz, 2H), 4.41–4.26 (m, 2H), 4.12–4.03 (m, 4H), 3.57–3.43 (m, 6H), 3.12–2.61 (m, 8H), 2.38–2.24 (m, 4H), 2.14–1.93 (m, 7H), 1.86–1.74 (m, 3H), 1.54–1.39 (m, 4H), 1.20 (bs, 8H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 95: Synthesis of N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6- yl]methyl]-12-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-12-oxo- dodecanamide (Compound 95):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (70 mg, 89.94 μmol, hydrochloric acid) and 12-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol- 6-yl]methylamino]-12-oxo-dodecanoic acid (C-16) (40.02 mg, 62.96 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (29.06 mg, 224.86 μmol, 39.17 μL) followed by HATU (51.30 mg, 134.92 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, ice- cold water (5 mL) was added to the reaction mixture to afford solid. A solid was filtered to afford crude product which was purified by prep-HPLC to afford N-[[1-(2,6-dioxo-3-piperidyl)-2-oxo- benzo[cd]indol-6-yl]methyl]-12-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-12-oxo- dodecanamide (Compound 95) (33 mg, 24.89 μmol, 27.67% yield, 97.39% purity, formic acid) as an yellow solid. Prep. HPLC condition: Column/dimensions: X-SELECT C18 (250*19*5 μ); Mobile phase A: 0.1% Formic acid in water (aq); Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/10 2/10 10/40 12/40 13/100 14/100 15/10 16/10; Flow rate: 17 mL/min; Solubility: ACN+THF+water; Spot visualization: UV active compound; LCMS [ES⁺]: m/z 1245.66 [M+H]⁺; Retention time (min): 1.67; ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 10.04 (bs, 1H), 9.18 (s, 1H), 8.36–8.30 (m, 2H), 8.19 (s, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.84 (t, J = 6.0 Hz, 1H), 7.77–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.39–7.32 (m, 2H), 7.10 (d, J = 7.6 Hz, 1H), 7.01 (s, 1H), 6.65 (s, 1H), 5.44 (d, J = 5.6 Hz, 1H), 5.36–5.17 (m, 3H), 4.69 (d, J = 5.6 Hz, 2H), 4.54 (bs, 2H), 4.42–4.22 (m, 2H), 4.17 (d, J = 5.6 Hz, 1H), 4.09 (d, J = 5.6 Hz, 1H), 3.98–3.88 (m, 2H), 3.62–3.50 (bs, 6H), 3.16–2.88 (m, 4H), 2.76–2.56 (m, 3H), 2.41–2.29 (m, 6H), 2.18–1.98 (m, 6H), 1.83–1.72 (m, 3H), 1.47 (bs, 4H), 1.20 (bs, 11H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 96: Synthesis of 1-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]phenyl]hexahydropyrimidine-2,4-dione (Compound 96): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (60 mg, 80.88 μmol) and 2-[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]-1-piperidyl]acetic acid (C-28) (21.44 mg, 64.71 μmol) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (31.36 mg, 242.65 μmol, 42.27 μL) followed by HATU (46.13 mg, 121.33 μmol) portion wise. The reaction mixture was stirred at 25 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude material was purified by prep-HPLC to afford product 1-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]phenyl]hexahydropyrimidine-2,4-dione (Compound 96) (10 mg, 9.23 μmol, 11.41% yield, 97.37% purity) as an off-white solid. Prep- HPLC condition: Column/dimensions: SUNFIRE C18 (150, 5μm); Mobile phase A: 0.1% TFA in water; Mobile phase B: CAN; Gradient (Time/%B): 0/15,2/15,10/30,14./30,14.1/98; Flow rate: 18mL/min; Solubility: THF+ACN+H₂O; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1055.53 [M+H]⁺; Retention time (min): 5.43; ¹H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.91 (s, 1H), 9.19 (s, 1H), 7.78–7.73 (q, J = 9.2, 6.4 Hz, 1H), 7.36–7.31 (m, 2H), 7.23 (bs, 4H), 7.01 (s, 1H), 6.65 (s, 1H), 5.37–5.16 (m, 3H), 4.56–4.25 (m, 4H), 4.16–3.91 (m, 4H), 3.74 (t, J = 6.4 Hz, 2H), 3.64 (bs, 4H), 3.49 (bs, 2H), 3.19 (bs, 2H), 3.12–2.66 (m, 8H), 2.45 (bs, 2H), 2.39 (bs, 2H), 2.16–1.94 (m, 6H), 1.86–1.58 (m, 7H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 97: Synthesis of 3-[6-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 97):

O N N N N N N O N F N N N O HN N O N O F OH F ^{Compound 97} To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (60 mg, 80.88 μmol) and 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1-piperidyl]acetic acid (C-23) (24.88 mg, 64.71 μmol) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (31.36 mg, 242.65 μmol, 42.27 μL) followed by addition of HATU (46.13 mg, 121.33 μmol) portion wise. Then reaction mixture was stirred at 25 °C for 12 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to afford crude product. The crude product was purified by Prep-HPLC to afford a product 3-[6-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]- 1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 97) (11 mg, 9.44 μmol, 11.67% yield, 95.09% purity) as off-white solid. Prep-HPLC condition: Column Name: X-SELECT C18; 250x19mm; 5μ; Mobile Phase-A: 0.10 % Formic acid in Water; Mobile Phase-B: Acetonitrile; Gradient program (T/%B): 0.1/10, 3/10, 7/35, 10/30, 10.10/95, 13/95; Flow Rate (mL/minute): 18; No. of Injection's: 12; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1108.41 [M+H]⁺; Retention time (min): 1.29; ¹H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 9.92 (s, 1H), 9.19 (s, 1H), 8.13 (s, 1H), 7.78–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.38–7.33 (m, 2H), 7.05–6.98 (m, 2H), 6.66 (s, 1H), 5.39–5.16 (m, 3H), 4.54–4.25 (m, 5H), 4.17–4.02 (m, 7H), 3.71–3.49 (m, 6H), 3.24–2.58 (m, 10H), 2.33 (bs, 4H), 2.24–1.98 (m, 7H), 1.85 (bs, 7H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 98: Synthesis of 1-[6-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl] h d l di i 2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (Compound 98): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (65 mg, 83.52 μmol, hydrochloric acid) and 2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl- indazol-6-yl]-1-piperidyl]acetic acid (C-25) (33.37 mg, 66.82 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (53.97 mg, 417.60 μmol, 72.74 μL) followed by HATU (47.63 mg, 125.28 μmol). The reaction mixture was stirred at 25 °C for 12 hours. The reaction progress was monitored by LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) solid was precipitated. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 1-[6-[1-[2-[4-[5-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]- 1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (Compound 98) (15.6 mg, 13.63 μmol, 16.32% yield, 96.89% purity)as an off-white solid. Prep-HPLC condition: Column Name: X- SELECT C18; 250 19 5 M bil Ph A 010 % F i id in Water; Mobile Phase- B: Acetonitrile; Gradient program (T/%B): 0.1/10, 3/10, 7/35, 10/30, 10.10/95, 13/95; Flow Rate (mL/minute): 18; No. of Injection's:12; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1109.43 [M+H]⁺; Retention time (min): 1.27; ¹H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 9.93 (s, 1H), 9.19 (s, 1H), 7.78–7.73 (q, J = 9.2, 6.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.42 (bs, 1H), 7.37–7.32 (m, 2H), 7.05–6.99 (m, 2H), 6.66 (s, 1H), 5.39–5.16 (m, 3H), 4.53 (bs, 2H), 4.42–4.23 (m, 2H), 4.17–4.04 (m, 3H), 3.99–3.87 (m, 6H), 3.78–3.57 (m, 4H), 3.50 (bs, 2H), 3.22 (bs, 2H), 3.13–2.94 (m, 6H), 2.84–2.59 (m, 4H), 2.32 (bs, 2H), 2.12–1.98 (m, 6H), 1.85– 1.69 (m, 7H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 99: Synthesis of 1-[6-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]-1,2-benzoxazol-3-yl]hexahydropyrimidine-2,4-dione (Compound 99): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[15-a][14]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (0.065 g, 83.52 μmol, hydrochloric acid) and 2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1,2- benzoxazol-6-yl]-1-piperidyl]acetic acid (C-26) (32.50 mg, 66.82 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (53.97 mg, 417.60 μmol, 72.74 μL) followed by HATU (47.63 mg, 125.28 μmol). The reaction mixture was stirred at 25 °C for 12 hours. The reaction progress was monitored ^by LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) solid was precipitated. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 1-[6-[1-[2-[4-[5-[7- (8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]- 1,2-benzoxazol-3-yl]hexahydropyrimidine-2,4-dione (Compound 99) (15 mg, 13.09 μmol, 15.68% yield, 95.68% purity) as an off-white solid. Prep-HPLC condition: Column Name: X- SELECT C18; 250x19mm; 5u; Mobile Phase-A: 0.10 % Formic acid in Water; Mobile Phase- B: Acetonitrile; Gradient program (T/%B): 0.1/10, 3/10, 7/35, 10/30, 10.10/95, 13/95; Flow Rate (mL/minute): 18; No. of Injection's:12; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1096.49 [M+H]⁺; Retention time (min): 5.52; ¹H NMR (400 MHz, DMSO-d6): δ 10.86 (bs, 1H), 9.93 (s, 1H), 9.19 (s, 1H), 7.78–7.73 (m, 2H), 7.57 (bs, 1H), 7.37–7.28 (m, 3H), 7.01 (d, J = 2.4 Hz, 1H), 6.66 (s, 1H), 5.38–5.16 (m, 3H), 4.53 (d, J = 6.0 Hz, 2H), 4.42–4.23 (m, 2H), 4.17–3.94 (m, 6H), 3.69–3.47 (m, 6H), 3.21 (bs, 2H), 3.14–2.94 (m, 6H), 2.84–2.68 (m, 4H), 2.33 (bs, 1H), 2.18–1.98 (m, 6H), 1.91–1.69 (m, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 100: Synthesis of 3-[6-[4-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-

1-yl]-2-oxo-ethyl]-1-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 100): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (0.065 g, 83.52 μmol, hydrochloric acid) and 2-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol- 6-yl]-4-piperidyl]acetic acid (C-33) (33.30 mg, 66.82 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) was added and DIPEA (53.97 mg, 417.60 μmol, 72.74 μL) and HATU (47.63 mg, 125.28 μmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. After completion, ice-cold water (5 mL) was added to the reaction mixture to afford precipitate, which was filtered to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[6-[4-[2-[4-[5-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-1-piperidyl]- 1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 100) (20 mg, 16.75 μmol, 20.06% yield, 96.67% purity, formic acid) as an off-white solid. Prep-HPLC Condition: Column/dimensions: X-SELECT C18 (19*250, 5μm); Mobile phase A: 0.1 % TFA in Water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/75, 3/75, 7/85, 12/85, 12.10/95, 14/95, 14.01/75, 16/75; Flow rate: 18 mL/min; Solubility: ACN+THF+Water; LCMS [ES⁺]: 1094.53 [M+H]⁺; Retention time (min): 1.42; ¹H NMR (400 MHz, DMSO-d6): δ 10.83 (bs, 1H), 10.62– 9.86 (bs, 1H), 9.19 (s, 1H), 7.78–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.37– 7.31 (m, 2H), 7.01 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 9.2 Hz, 1H), 6.82 (s, 1H), 6.66 (s, 1H), 5.38– 5.16 (m, 3H), 4.52 (d, J = 5.6 Hz, 2H), 4.42–4.23 (m, 3H), 4.17–3.94 (m, 4H), 3.87 (s, 3H), 3.76 (d, J = 12.0 Hz, 2H), 3.64–3.48 (m, 6H), 3.14–2.99 (m, 4H), 2.85–2.58 (m, 5H), 2.39–2.24 (m, 5H), 2.17–1.97 (m, 5H), 1.92–1.73 (m, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 101: Synthesis of 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]phenoxy]piperidine-2,6-dione (Compound 101): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-123567-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (60 mg, 80.88 μmol) and 2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]-1-piperidyl]acetic acid (C- 18) (22.41 mg, 64.71 μmol) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (31.36 mg, 242.65 μmol, 42.27 μL) followed by addition of HATU (46.13 mg, 121.33 μmol) portion wise. Then reaction mixture was stirred at 25 °C for 12 hours. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to afford crude product. The crude product was purified by SFC to afford a product 3-[4-[1-[2-[4-[5-[7- (8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4- piperidyl]phenoxy]piperidine-2,6-dione (Compound 101) (7.56 mg, 6.19 μmol, 7.65% yield, 96.96% purity, trifluoroacetic acid) as off-white solid. Prep-HPLC Condition: Column Name: X-SELECT C18; 250 x 19 mm; 5μ; Mobile Phase-A: 0.10 % Formic acid in water; Mobile Phase-B: Acetonitrile; Gradient program (T/%B): 0.1/10, 3/10, 7/35, 10/30, 10.10/95, 13/95; Flow Rate (mL/minute): 18; No. of Injection's:12; LCMS [ES⁺]: m/z 1070.54 [M+H]⁺; Retention time (min): 5.58; ¹H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1H), 9.93 (s, 1H), 9.21 (s, 1H), 7.79–7.74 (q, J = 9.2, 6.4 Hz, 1H), 7.38–7.32 (m, 2H), 7.17–7.13 (bs, 2H), 7.03–6.92 (m, 3H), 6.68 (bs, 1H), 5.34–5.11 (m, 4H), 4.52 (d, J = 5.6 Hz, 2H), 4.43–4.26 (m, 3H), 4.18–3.92 (m, 4H), 3.84–3.47 (m, 9H), 3.22–2.84 (m, 8H), 2.73–2.61 (m, 2H), 2.42–2.33 (m, 2H), 2.22–1.68 (m, 13H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 102: Synthesis of 3-[5-[4-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-

1-yl]-2-oxo-ethyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 102): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (0.06 g, 77.09 μmol, hydrochloric acid) and 2-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-4-piperidyl]acetic acid (C-32) (31.73 mg, 61.68 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (49.82 mg, 385.47 μmol, 67.14 μL) followed by HATU (43.97 mg, 115.64 μmol) portion wise. The reaction mixture was stirred at 25 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[4-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-1- piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 102) (15.8 mg, 13.67 μmol, 17.73% yield, 97.24% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: SUNFIRE C18 (150, 5μm); Mobile phase A: 0.1% TFA in water; Mobile phase B: ACN; Gradient (Time/%B): 0/15,2/15,10/30,14./30,14.1/98; Flow rate: 18mL/min; Solubility: THF+ACN+H2O; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1124.41 [M+H]⁺; Retention time (min): 1.40; ¹H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 9.93 (s, 1H), 9.19 (s, 1H), 7.79–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.38–7.32 (m, 2H), 7.00 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.81 (s, 1H), 6.65 (s, 1H), 6.62 (d, J = 8.0 Hz, 1H), 5.38–5.14 (m, 4H), 4.52 (d, J = 5.2 Hz, 2H), 4.41–4.24 (m, 2H), 4.16–3.92 (m, 4H), 3.64–3.47 (m, 8H), 3.29 (s, 3H), 3.14–2.98 (m, 3H), 2.94–2.79 (m, 2H), 2.68–2.56 (m, 4H), 2.32 (bs, 5H), 2.17– 1.90 (m, 6H), 1.88–1.72 (m, 6H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 103: Synthesis of 3-[6-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 103): O O N N N N N NH HO O _C-29 O N O F N H HATU, DIPEA, DMF, RT, 16h N N N O F N OH F A^-6

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (75 mg, 96.37 μmol, hydrochloric acid) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol- 6-yl]-1-piperidyl]acetic acid (C-29) (41.28 mg, 77.09 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (37.36 mg, 289.11 μmol, 50.36 μL) followed by HATU (54.96 mg, 144.55 μmol) portion wise. The reaction mixture was stirred at 25 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[6-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]- 2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 103) (16 mg, 12.78 μmol, 13.26% yield, 91.47% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: Sunfire C18 (150, 5μm); Mobile phase A: 0.1% TFA in water; Mobile phase B: CAN; Gradient (Time/%B): 0/15, 2/15, 10/30, 14./30, 14.1/98; Flow rate: 18 mL/min; Solubility: THF+ACN+H2O; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1145.58 [M+H]⁺; Retention time (min): 5.77; ¹H NMR (400 MHz, DMSO-d6):δ 11.12 (s, 1H), 9.97 (s, 1H), 9.20 (s, 1H), 8.03 (d, J = 6.4 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.78–7.67 (m, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.37–7.31 (m, 2H), 7.15 (d, J = 7.2 Hz, 1H), 7.01 (s, 1H), 6.66 (bs, 1H), 5.47–5.16 (m, 4H), 4.52 (bs, 2H), 4.41–4.26 (m, 2H), 4.16–4.04 (m, 3H), 3.97 (bs, 1H), 3.72–3.49 (m, 6H), 3.42–3.24 (m, 3H), 3.12–2.99 (m, 6H), 2.86–2.66 (m, 3H), 2.29 (bs, 5H), 2.16–1.95 (m, 5H), 1.91–1.74 (m, 7H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 104: Synthesis of 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]phenyl]piperidine-2,6-dione (Compound 104): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (65 mg, 83.52 μmol, hydrochloric acid) and 2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1- piperidyl]acetic acid (C-27) (29.69 mg, 66.82 μmol, trifluoroacetic acid) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (32.38 mg, 250.56 μmol, 43.64 μL) followed by HATU (47.63 mg, 125.28 μmol) portion wise. The reaction mixture was stirred at 25 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4- piperidyl]phenyl]piperidine-2,6-dione (Compound 104) (11 mg, 9.67 μmol, 11.58% yield, 92.69% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: SUNFIRE C18 (150, 5μm); Mobile phase A: 0.1% TFA in water; Mobile phase B: CAN; Gradient (Time/%B): 0/15,2/15,10/30,14./30,14.1/98; Flow rate: 18 mL/min; Solubility: THF+ACN+H₂O; Spot visualization: UV active compound; LCMS (ES⁺): m/z 1054.58 [M+H]⁺; Retention time (min): 5.77; 1H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 10.12–9.94 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.18 (bs, 2H), 7.12 (d, J = 7.6 Hz, 2H), 7.01 (d, J = 2.0 Hz, 1H), 6.65 (s, 1H), 5.36–5.15 (m, 3H), 4.52 (d, J = 6.0 Hz, 2H), 4.42–4.25 (m, 2H), 4.16–3.99 (m, 3H), 3.93 (bs, 1H), 3.83–3.77 (m, 1H), 3.68–3.56 (m, 4H), 3.57 (bs, 2H), 3.18 (bs, 2H), 3.12–3.06 (m, 2H), 3.03–2.88 (m, 3H), 2.85–2.78 (m, 1H), 2.68–2.58 (m, 2H), 2.33 (bs, 5H), 2.18–1.97 (m, 8H), 1.86 (bs, 2H), 1.82–1.55 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 105: Synthesis of 3-[7-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 105):

To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (60 mg, 80.88 μmol)and 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-7-yl]-1-piperidyl]acetic acid (C-24) (32.25 mg, 64.71 μmol, trifluoroacetic acid)in N,N-dimethylformamide (1 mL)at 0 ^oC was added DIPEA (31.36 mg, 242.65 μmol, 42.26 μL) followed by addition of HATU (46.13 mg, 121.33 μmol) portion wise. The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[7-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 105) (11 mg, 9.24 μmol, 11.43% yield, 93.13% purity) as an off-white solid. Prep- HPLC condition: Column/dimensions: X-SELECT C18 (19*250*5μm); Mobile phase A: 10 mM Ammonium acetate in water (Aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B):0/10, 2/20, 10/60, 13/60; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1108.65 [M+H]⁺; Retention time (min): 5.44; ¹H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 10.14–9.96 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.24 (bs, 1H), 7.06–6.99 (m, 2H), 6.63 (s, 1H), 5.37–5.15 (m, 3H), 4.53 (d, J = 5.6 Hz, 1H), 4.38–4.27 (m, 3H), 4.20 (s, 3H), 4.17–4.02 (m, 3H), 3.96 (bs, 1H), 3.68–3.56 (m, 4H), 3.50 (bs, 2H), 3.23 (bs, 2H), 3.11–2.95 (m, 5H), 2.85–2.78 (m, 1H), 2.68–2.57 (m, 3H), 2.38–2.21 (m, 5H), 2.17–1.94 (bs, 5H), 1.91– 1.68 (m, 9H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 106: Synthesis of 3-[8-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]-2,3-dihydro-1,4-benzoxazin-4-yl]piperidine-2,6-dione (Compound 106): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (70 mg, 89.94 μmol, hydrochloric acid)and 2-[4-[4-(2,6-dioxo-3-piperidyl)-2,3-dihydro-1,4- benzoxazin-8-yl]-1-piperidyl]acetic acid (C-31) (36.08 mg, 71.96 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (58.12 mg, 449.72 μmol, 78.33 μL) followed by addition HATU (51.30 mg, 134.92 μmol) The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[8-[1-[2-[4-[5-[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin 1 l] 2 h l] 4 i id l] 23 dih d 14 b nzoxazin-4- yl]piperidine-2,6-dione (Compound 106) (15 mg, 13.03 μmol, 14.48% yield, 96.51% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*150*5μm); Mobile phase A: 10mM Ammonium acetate in water (Aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B):0/10, 2/10, 10/45, 13/45; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1111.60 [M+H]⁺; Retention time (min): 1.46; ¹H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 10.14–9.92 (bs, 1H), 9.19 (s, 1H), 7.78– 7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.38–7.31 (m, 2H), 7.01 (d, J = 2.0 Hz, 1H), 6.65 (bs, 3H), 6.46 (bs, 1H), 5.36–5.15 (m, 3H), 4.91–4.85 (m, 1H), 4.52 (d, J = 5.6 Hz, 2H), 4.41–4.22 (m, 2H), 4.18–3.89 (m, 6H), 3.64–3.46 (m, 6H), 3.25–3.14 (m, 4H), 3.11–2.98 (m, 4H), 2.93–2.76 (m, 5H), 2.57 (bs, 2H), 2.42–2.24 (m, 3H), 2.15–1.94 (m, 7H), 1.91–1.75 (m, 6H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 107: Synthesis of 3-[5-[1-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine- 1-carbonyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 113):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL) was added DIPEA (63.70 mg, 492.86 μmol, 85.84 μL) and HATU (56.22 mg, 147.86 μmol) at 0 °C. After 5 minutes, 3-[3- methyl-2-oxo-5-[1-(piperazine-1-carbonyl)-4-piperidyl]benzimidazol-1-yl]piperidine-2,6- dione (C-91) (48.40 mg, 98.57 μmol, hydrochloric acid) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 12 hours. The progress of reaction was monitored by TLC and LCMS. After completion, ice-cold water (3 mL) was added to the reaction mixture and lyophilized to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[5-[1-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carbonyl]-4-piperidyl]-3- methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 113) (16 mg, 13.31 μmol, 13.50% yield, 92.33% purity) as an off-white solid. Prep- HPLC conditions: Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A: 10 mM Ammonium acetate in water (Aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/25, 10/75; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS [ES⁺]: 1110.62 [M+H]⁺; Retention time (min): 5.35; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 10.06– 9.95 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.37–7.31 (m, 2H), 7.10 (s, 1H), 7.01 (d, J = 6.0 Hz, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.64 (s, 1H), 5.36–5.15 (m, 4H), 4.52 (d, J = 5.6 Hz, 2H), 4.41–4.25 (m, 2H), 4.16–4.05 (m, 2H), 3.97 (bs, 2H), 3.75 (d, J = 12.4 Hz, 2H), 3.62 (bs, 2H), 3.33 (s, 3H), 3.20 (bs, 4H), 3.12–3.01 (m, 3H), 2.94–2.78 (m, 4H), 2.74–2.60 (m, 3H), 2.47 (bs, 2H), 2.35 (bs, 2H), 2.15–1.97 (m, 5H), 1.88–1.74 (m, 4H), 1.71–1.58 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 108: Synthesis of 3-[5-[7-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-2,7- diazaspiro[3.5]nonan-2-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 114): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL) was added DIPEA (63.70 mg, 492.86 μmol, 85.84 μL) and HATU (56.22 mg, 147.86 μmol) at 0 °C. After 5 minutes 3-[5-(2,7- diazaspiro[3.5]nonan-2-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (B-71) (41.39 mg, 98.57 μmol, hydrochloric acid) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. To the reaction mixture, ice-cold water (5 mL) was added and lyophilized to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[5-[7-[5-[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6- dione (Compound 114) (15 mg, 12.84 μmol, 13.02% yield, 88.92% purity) as an off-white solid. Prep-HPLC conditions: Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A: 10 mM ammonium acetate in water (aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/25, 10/75; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS [ES⁺]: 1039.53 [M+H]⁺; Retention time (min): 1.47; ¹H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 10.08–10.01 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.37–7.31 (m, 2H), 7.01 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.60 (s, 1H), 6.30 (d, J = 2.0 Hz, 1H), 6.11 (q, J = 8.4, 1.6 Hz, 1H), 5.36–5.15 (m, 4H), 4.51 (d, J = 6.0 Hz, 2H), 4.41–4.25 (m, 2H), 4.16–4.05 (m, 2H), 3.87 (bs, 2H), 3.58 (bs, 6H), 3.27 (s, 3H), 3.12–3.0 (m, 3H), 2.94–2.79 (m, 2H), 2.64–2.57 (m, 2H), 2.40 (bs, 2H), 2.16–1.95 (m, 5H), 1.85–1.72 (m, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 109: Synthesis of 3-[5-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3- azaspiro[5.5]undecan-9-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 115):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL) was added DIPEA (63.70 mg, 492.86 μmol, 85.84 μL) and HATU (56.22 mg, 147.86 μmol) at 0 °C. After 5 minutes, 3-[5-(3- azaspiro[5.5]undecan-9-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (B-70) (44.06 mg, 98.57 μmol, hydrochloric acid) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. To the reaction mixture, ice-cold water (5 mL) was added and lyophilized to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[5-[3-[5-[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-3-azaspiro[5.5]undecan-9-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6- dione (Compound 115) (21 mg, 19.35 μmol, 19.63% yield, 98.24% purity) as an off-white solid. Prep-HPLC Conditions: Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A: 0.1% Ammonium acetate in water (Aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/20, 12/65; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS [ES⁺]: 1066.56 [M+H]⁺; Retention time (min): room temperature: 1.70; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.92 (s, 1H), 9.20 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.38–7.32 (m, 2H), 7.11 (bs, 1H), 7.02–6.96 (m, 2H), 6.91 (bs, 1H), 6.57 (s, 1H), 5.34–5.20 (m, 4H), 4.51 (d, J = 5.6 Hz, 2H), 4.41–4.25 (m, 2H), 4.16–4.05 (m, 2H), 3.88 (bs, 2H), 3.60 (bs, 2H), 3.31 (s, 3H), 3.14–3.02 (m, 3H), 2.94–2.79 (m, 2H), 2.74–2.53 (m, 2H), 2.49 (bs, 2H), 2.33 (bs, 2H), 2.16–1.95 (m, 5H), 1.89–1.75 (m, 4H), 1.63 (bs, 7H), 1.34 (d, J = 6.2 Hz, 2H), 1.23 (d, J = 5.8 Hz, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 110: Synthesis of 3-[5-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 116): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid)and 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine- 2,6-dione (B-28) (37.34 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (63.70 mg, 492.86 μmol, 85.84 μL) followed by HATU (56.22 mg, 147.86 μmol) portion wise. The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[1-[5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido ,5-a][1,4]diazepine-2- carbonyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 116) (19 mg, 18.25 μmol, 18.52% yield, 95.88% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A: 10 mM Ammonium acetate in water (Aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B):0/10, 2/10, 15/100; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS [ES⁺]: m/z 998.52 [M+H]⁺; Retention time (min): 1.56; ¹H NMR (400 MHz, DMSO- d6):δ 11.07 (s, 1H), 10.02 (s, 1H), 9.20 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.10 (s, 1H), 7.04–6.98 (m, 2H), 6.91 (d, J = 8.8 Hz, 1H), 6.63 (s, 1H), 5.36–5.16 (m, 4H), 4.88–4.82 (m, 1H), 4.67–4.59 (m, 1H), 4.52 (d, J = 6.0 Hz, 2H), 4.31–4.26 (m, 2H), 4.16– 4.06 (m, 2H), 3.31 (s, 3H), 3.17–3.03 (m, 4H), 2.93–2.78 (m, 4H), 2.71–2.58 (m, 2H), 2.40 (bs, 2H), 2.13–1.96 (m, 5H), 1.88–1.74 (m, 6H), 1.66–1.54 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 111: Synthesis of 3-[5-[1-[2-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]acetyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 117):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid)and 3-[3-methyl-2-oxo-5-[1-[2-(4-piperidyl)acetyl]-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-94) (49.68 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (63.70 mg, 492.86 μmol, 85.84 μL) followed by addition HATU (56.22 mg, 147.86 μmol). The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[1- [2-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]acetyl]-4-piperidyl]-3- methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 117) (15 mg, 12.69 μmol, 12.88% yield, 95.06% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-SELECT C18 (19*250*5μm); Mobile phase A: 10mM Ammonium acetate in water (Aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B):0/10, 2/20, 10/60, 13/60; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1123.57 [M+H]⁺; Retention time (min): 1.56; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.94 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.09 (s, 1H), 7.02–6.99 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.56 (s, 1H), 5.36–5.15 (m, 4H), 4.62–4.23 (m, 7H), 4.16–3.97 (m, 3H), 3.31 (s, 3H), 3.15–3.01 (m, 5H), 2.94–2.69 (m, 5H), 2.63–2.56 (m, 2H), 2.39 (bs, 4H), 2.14–1.97 (m, 6H), 1.86–1.67 (bs, 8H), 1.64–1.49 (m, 2H), 1.17–1.06 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 112: Synthesis of 3-[5-[1-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperidine- 4-carbonyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 118): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) and 3-[3-methyl-2-oxo-5-[1-(piperidine-4-carbonyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-95) (48.30 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (63.70 mg, 492.86 μmol, 85.84 μL) followed b dditi f HATU (5622 14786 l) The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[1- [1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperidine-4-carbonyl]-4-piperidyl]-3- methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 118) (22 mg, 18.92 μmol, 19.20% yield, 95.41% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-SELECT C18 (19*250*5μm); Mobile phase A: 10 mM Ammonium acetate in water (Aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/20, 10/60, 13/60; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1109.66 [M+H]⁺; Retention time (min): 1.56; ¹H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.95 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.10 (s, 1H), 7.03–6.99 (m, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 5.37–5.15 (m, 4H), 4.68–4.22 (m, 7H), 4.17–4.04 (m, 3H), 3.31 (s, 3H), 3.15–3.01 (m, 6H), 2.94–2.71 (m, 5H), 2.63–2.56 (m, 2H), 2.39 (bs, 2H), 2.14–1.95 (m, 5H), 1.78–1.47 (bs, 12H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 113: Synthesis of 3-[5-[1-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 119):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid)and 3-[3-methyl-2-oxo-5-[1-(4-piperidyl)-4-piperidyl]benzimidazol-1- yl]piperidine-2,6-dione (C-37) (45.54 mg, 98.57 μmol, hydrochloric acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (63.70 mg, 492.86 μmol, 85.85 μL) followed by addition of HATU (56.22 mg, 147.86 μmol) . The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[1-[1-[5-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]-4-piperidyl]-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (Compound 119) (12 mg, 10.31 μmol, 10.46% yield, 92.90% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE- C18; 150x20mm; 5μ; Mobile phase A: 10 mM Ammonium acetate in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/10, 2/15, 10/45, 12/46; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1081.57 [M+H]⁺; Retention time (min): 1.41; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 10.06–9.97 (bs, 1H), 9.20 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.08 (s, 1H), 7.02–6.95 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.58 (s, 1H), 5.37–5.15 (m, 4H), 4.73–4.65 (m, 1H), 4.51 (d, J = 6.0 Hz, 3H), 4.42–4.24 (m, 2H), 4.15–4.03 (m, 2H), 3.31 (s, 3H), 3.14–3.02 (m, 4H), 2.97–2.79 (m, 4H), 2.75–2.69 (m, 1H), 2.63–2.54 (m, 5H), 2.43–2.31 (m, 3H), 2.25 (d, J = 10.4 Hz, 2H), 2.13–1.94 (m, 5H), 1.84– 1.59 (m, 8H), 1.42–1.33 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 114: Synthesis of 3-[5-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 120): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) and 3-[3-methyl-2-oxo-5-[1-(2-piperazin-1-ylethyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-88) (38.72 mg, 78.86 μmol, hydrochloric acid) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (63.70 mg, 492.86 μmol, 85.85 μL) followed by addition of HATU (56.22 mg, 147.86 μmol) . The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[1- [2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]ethyl]-4-piperidyl]-3- methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 120) (22 mg, 17.84 μmol, 18.10% yield, 90.02% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE-C18; 150x20mm; 5μ; Mobile phase A: 10 mM Ammonium acetate in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/10, 2/15, 10/45, 12/46; Flow rate: 18 mL/min ; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1110.65 [M+H]⁺; Retention time (min): 1.36; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 10.08–9.96 (bs, 1H), 9.19 (s, 1H), 7.78– 7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.38–7.32 (m, 2H), 7.09 (s, 1H), 7.02–6.96 (m, 2H), 6.90 (d, J = 8.4 Hz, 1H), 6.60 (s, 1H), 5.38–5.16 (m, 4H), 4.51 (d, J = 5.6 Hz, 2H), 4.42–4.24 (m, 2H), 4.15– 4.05 (m, 2H), 3.91 (bs, 2H), 3.57 (bs, 2H), 3.31 (bs, 3H), 3.14–2.79 (m, 8H), 2.73–2.58 (m, 3H), 2.47–2.39 (m, 8H), 2.33 (bs, 2H), 2.16–1.95 (m, 8H), 1.88–1.64 (m, 6H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 115: Synthesis of 3-[5-[1-[2-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]-2-oxo-ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6- dione (Compound 121):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid)and 3-[3-methyl-2-oxo-5-[1-[2-oxo-2-(4-piperidyl)ethyl]-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-90) (49.68 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (63.70 mg, 492.86 μmol, 85.84 μL) followed by addition HATU (56.22 mg, 147.86 μmol) portion wise. The reaction mixture was stirred at 25 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[1-[2-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]-2- oxo-ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 121) (21 mg, 16.57 μmol, 16.81% yield, 88.65% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*150*5μm); Mobile phase A: 10 mM Ammonium acetate in water (Aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/10, 10/45, 13/45; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1123.62 [M+H]⁺; Retention time (min): 5.45; ¹H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.96 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.37–7.31 (m, 2H), 7.09 (s, 1H), 7.02–6.98 (m, 2H), 6.59 (s, 1H), 6.91 (d, J = 8.0 Hz, 1H), 5.38–5.15 (m, 4H), 4.67– 4.23 (m, 6H), 4.16–4.05 (m, 2H), 3.31 (bs, 5H), 3.21–3.00 (m, 4H), 2.94–2.77 (m, 6H), 2.73– 2.58 (m, 3H), 2.33 (bs, 2H), 2.11–2.06 (m, 4H), 2.05–1.96 (m, 3H), 1.88–1.71 (m, 10H), 1.44– 1.33 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 116: Synthesis of 3-[5-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]acetyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 122): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) and 3-[3-methyl-2-oxo-5-[1-(2-piperazin-1-ylacetyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-93) (49.78 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL)at 0 °C was added DIPEA (63.70 mg, 492.86 μmol, 85.85 μL) followed by addition of HATU (56.22 mg, 147.86 μmol). The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[1- [2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]acetyl]-4-piperidyl]-3- methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 122) (14 mg, 11.38 μmol, 11.55% yield, 91.41% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A: 0.1% Ammonium acetate in water (Aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/15, 10/70; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1124.57 [M+H]⁺; Retention time (min): 5.18; ¹H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 10.03 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.38–7.32 (m, 2H), 7.08 (s, 1H), 7.03–6.98 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.60 (s, 1H), 5.37–5.15 (m, 4H), 4.51 (d, J = 5.2 Hz, 3H), 4.42–4.24 (m, 2H), 4.18–4.05 (m, 3H), 3.93 (bs, 2H), 3.60 (bs, 2H), 3.26 (bs, 4H), 3.18–3.03 (m, 5H), 2.94–2.75 (m, 3H), 2.74–2.57 (m, 3H), 2.46–2.31 (m, 6H), 2.16–1.94 (m, 5H), 1.86–1.59 (m, 7H), 1.58– 1.46 (m, 1H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 117: Synthesis of N-[3-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]propyl]-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-N-methyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxamide (Compound 123):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid)and 3-[3-methyl-5-[1-[3-(methylamino)propyl]-4-piperidyl]-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (C-100) (40.76 mg, 90.58 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL)at 0 °C was added DIPEA (63.70 mg, 492.86 μmol, 85.84 μL)followed by addition of HATU (56.22 mg, 147.86 μmol). The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product N-[3-[4-[1-(2,6- dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]propyl]-5-[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-N-methyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (Compound 123) (28 mg, 24.14 μmol, 24.49% yield, 92.19% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-SELECT C18 (19*250*5μm); Mobile phase A: 10 mM Ammonium acetate in water (Aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/20, 10/60, 13/60; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1069.59 [M+H]⁺; Retention time (min): 5.45; ¹H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.96 (bs, 1H), 9.19 (s, 1H), 7.78–7.73 (q, J = 8.8, 6.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.09–6.85 (m, 4H), 6.60 (d, J = 7.6 Hz, 1H), 5.36– 5.14 (m, 4H), 4.51 (d, J = 5.6 Hz, 1H), 4.41–4.23 (m, 2H), 4.16–4.05 (m, 2H), 3.67 (bs, 1H), 3.43 (bs, 1H), 3.27 (bs, 5H), 3.12–3.04 (m, 2H), 3.01–2.78 (m, 8H), 2.72–2.60 (m, 3H), 2.30 (bs, 2H), 2.26–1.93 (m, 7H), 1.88 (s, 3H), 1.84–1.59 (m, 8H), 0.70 (t, J = 7.6 Hz, 3H). Synthesis 118: Synthesis of N-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]ethyl]-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-N-methyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxamide (Compound 124): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid)and 3-[3-methyl-5-[1-[2-(methylamino)ethyl]-4-piperidyl]-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (C-99) (42.97 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL)at 0 °C was added DIPEA (63.70 mg, 492.86 μmol, 85.84 μL) followed by addition of HATU (56.22 mg, 147.86 μmol). The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product N-[2-[4-[1-(2,6-dioxo- 3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]ethyl]-5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-N-methyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (Compound 124) (9 mg, 7.72 μmol, 7.83% yield, 90.51% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-SELECT C18 (19*250*5μm); Mobile phase A: 10 mM Ammonium acetate in water (Aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/20, 10/60, 13/60; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1055.60 [M+H]⁺; Retention time (min): 5.33; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.97 (bs, 1H), 9.18 (s, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.37–7.31 (m, 2H), 7.12–6.79 (m, 4H), 6.60 (bs, 1H), 5.37–5.15 (m, 4H), 4.51 (bs, 2H), 4.38–4.26 (m, 2H), 4.16–4.05 (m, 2H), 3.80 (bs, 1H), 3.54 (bs, 1H), 3.28 (bs, 4H), 3.11– 2.97 (m, 7H), 2.90–2.78 (m, 3H), 2.73–2.56 (m, 4H), 2.42–2.26 (m, 4H), 2.15–1.94 (m, 6H), 1.89 (s, 3H), 1.84–1.69 (m, 5H), 1.65–1.54 (m, 2H). Synthesis 119: Synthesis of N-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]butyl]-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-N-methyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxamide (Compound 125):

To stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (75 mg, 111.33 μmol) and 3-[3-methyl-5-[1-[4-(methylamino)butyl]-4-piperidyl]-2-oxo-benzimidazol-1- yl]piperidine-2,6-dione (C-101) (47.60 mg, 111.33 μmol) in N,N-dimethylformamide (1.5 mL) at room temperature was added HATU (63.50 mg, 166.99 μmol) followed by DIPEA (71.94 mg, 556.64 μmol, 96.95 μL) stirred at room temperature for 12 hours. The reaction was monitored by TLC and LCMS. To the reaction mixture was added water (1 mL) solid was precipitated. A solid was filtered to afford crude product. The crude product product was purified by Prep-HPLC to obtain product N-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]butyl]-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-N-methyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 125) (12 mg, 9.97 μmol, 8.96% yield, 90.01% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A: 10mM Ammonium acetate in water (aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/10,15/100; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS [ES⁺]: m/z 1083.65 [M+H]⁺; Retention time (min): 5.55; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 10.22–9.86 (bs, 1H), 9.19 (s, 1H), 7.78–7.73 (q, J = 9.2, 6.0 Hz, 1H), 7.37–7.31 (m, 2H), 7.08–6.96 (m, 3H), 6.92–6.84 (m, 1H), 6.61–6.56 (m, 1H), 5.34–5.14 (m, 4H), 4.51 (d, J = 6.0 Hz, 2H), 4.41–4.24 (m, 2H), 4.15– 4.04 (m, 2H), 3.68 (bs, 1H), 3.41 (bs, 1H), 3.24 (bs, 4H), 3.11–2.90 (m, 6H), 2.87–2.78 (m, 3H), 2.69–2.55 (m, 2H), 2.46–2.30 (m, 5H), 2.18–1.89 (m, 8H), 1.84–1.52 (m, 11H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 120: Synthesis of 3-[5-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 126): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) and 3-(3-methyl-2-oxo-5-piperazin-1-yl-benzimidazol-1- yl)piperidine-2,6-dione (B-29) (33.85 mg, 89.11 μmol, hydrochloric acid) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (38.22 mg, 295.71 μmol, 51.51 μL) followed by addition HATU (56.22 mg, 147.86 μmol) The reaction mixture was stirred at 25 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[4-[5-[7- (8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (Compound 126) (20 mg, 18.78 μmol, 19.05% yield, 93.81% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*150*5μm); Mobile phase A: 10 mM Ammonium acetate in water (AQ); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B: 0/10, 2/10, 10/45, 13/45; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 999.58 [M+H]⁺; Retention time (min): 1.47; ¹H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 10.07–9.92 (s, 1H), 9.20 (s, 1H), 7.78– 7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.38–7.32 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.69–6.63 (m, 2H), 5.35–5.14 (m, 4H), 4.57–4.47 (m, 2H), 4.41–4.24 (m, 2H), 4.18–4.05 (m, 4H), 3.76 (bs, 2H), 3.30 (bs, 3H), 3.15–2.99 (m, 7H), 2.89–2.76 (m, 2H), 2.69– 2.57 (m, 2H), 2.40–2.31 (m, 3H), 2.14–1.93 (m, 4H), 1.86–1.72 (m, 4H), 0.71 (t, J = 6.8 Hz, 3H). Synthesis 121: Synthesis of 3-[4-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]anilino]piperidine-2,6-dione (Compound 127):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL) was added DIPEA (63.70 mg, 492.86 μmol, 85.84 μL) and HATU (56.22 mg, 147.86 μmol) at 0 °C. After 5 minutes 3-[4-(4- piperidyl)anilino]piperidine-2,6-dione (B-81) (31.92 mg, 98.57 μmol, hydrochloric acid) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. To the reaction mixture, ice-cold water (5 mL) was added to the reaction mixture and lyophilized to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[4-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 127) (25 mg, 25.20 μmol, 25.57% yield, 95.07% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A: 0.1% Ammonium acetate in water (AQ); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/20, 12/65; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS [ES+]: 943.48 [M+H]⁺; Retention time (min): room temperature: 1.58; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 9.93 (s, 1H), 9.20 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.38–7.32 (m, 2H), 7.01 (s, 1H), 6.94 (d, J = 8.0 Hz, 2H), 6.60 (d, J = 8.0 Hz, 3H), 5.66 (d, J = 7.2 Hz, 1H), 5.27–5.20 (m, 3H), 4.76 (bs, 1H), 4.62–4.48 (m, 3H), 4.38–4.22 (m, 3H), 4.17–4.05 (m, 2H), 3.14–3.02 (m, 4H), 2.85–2.70 (m, 4H), 2.63–2.57 (m, 2H), 2.40–2.31 (m, 2H), 2.15–1.96 (m, 5H), 1.84–1.69 (m, 6H), 1.47 (bs, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 122: Synthesis of 3-[5-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 128) To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) and 3-[3-methyl-2-oxo-5-[1-(4-piperidylmethyl)-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-46) (46.92 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (2 mL) at 0 °C was added DIPEA (63.70 mg, 492.86 μmol, 85.84 μL) followed by addition HATU (56.22 mg, 147.86 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]methyl]-4-piperidyl]-3- methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 128) (17 mg, 15.00 μmol, 15.22% yield, 96.64% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*150*5μm); Mobile phase A: 10 mM Ammonium acetate in water (AQ); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/10, 10/45, 13/45; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1095.56 [M+H]⁺;Retention time (min): 1.42; ¹H NMR (400 MHz, DMSO-d6): 11.82–9.54 (bs, 2H), 9.20 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.38–7.31 (m, 2H), 7.09 (s, 1H), 7.03–6.96 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.56 (s, 1H), 5.37–5.14 (m, 4H), 4.52–4.33 (m, 5H), 4.31–4.06 (m, 3H), 3.31 (bs, 3H), 3.14–2.89 (m, 7H), 2.85–2.59 (m, 3H), 2.36 (bs, 2H), 2.18–2.09 (m, 4H), 2.06–1.94 (m, 6H), 1.91–1.84 (m, 8H), 1.82–1.63 (m, 6H), 0.71 (t, J = 7.2 Hz, 3H). The following degraders are prepared using the method described above in Compound 128 synthesis, with the corresponding carboxylic acid. Compound Compound Structure Compound 129

Compound 130 Synthesis 123: Synthesis of 3-[5-[1-[2-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 131):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (80 mg, 112.65 μmol, hydrochloric acid)and 3-[3-methyl-2-oxo-5-[1-[2-(4-piperidyl)ethyl]-4- piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (C-76) (55.20 mg, 112.65 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (72.80 mg, 563.27 μmol, 98.11 μL) followed by addition HATU (64.25 mg, 168.98 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[1-[2-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]ethyl]-4-piperidyl]-3-methyl- 2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 131) (26 mg, 21.55 μmol, 19.13% yield, 91.96% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X- BRIDGE C18 (19*150*5μm); Mobile phase A: 10 mM Ammonium acetate in water (AQ); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/10, 10/45, 13/45; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF. LCMS (ES⁺): m/z 1109.62 [M+H]⁺; Retention time (min): 1.43.¹H NMR (400 MHz, DMSO-d6): 11.08 (s, 1H), 10.14–9.88 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.37–7.31 (m, 2H), 7.09 (s, 1H), 7.02–6.96 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.56 (s, 1H), 5.37–5.13 (m, 4H), 4.62–4.22 (m, 6H), 4.15–4.04 (m, 2H), 3.31 (bs, 3H), 3.13–2.71 (m, 10H), 2.63–2.52 (m, 3H), 2.37–2.26 (m, 5H), 2.12–1.91 (m, 7H), 1.89–1.82 (m, 4H), 1.80–1.54 (m, 9H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 124: Synthesis of 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]acetyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 132): To stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) and 3-[4-[1-(2-piperazin-1-ylacetyl)-4-piperidyl]anilino]piperidine- 2,6-dione (C-97) (44.35 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL) at room temperature was added HATU (56.22 mg, 147.86 μmol) followed by DIPEA (63.70 mg, 492.86 μmol, 85.85 μL) stirred at room temperature for 12 hours. The reaction was monitored by TLC and LCMS. To the reaction mixture was added water (1 mL) solid was precipitated. A solid was filtered to afford crude product. The crude product was purified by Prep-HPLC to obtain product 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1- yl]acetyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 132) (24 mg, 21.37 μmol, 21.68% yield, 95.20% purity) as an off-white solid. Prep-HPLC Condition: Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A: 10mM Ammonium acetate in water (AQ); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B):0/10, 2/10, 15/100; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS [ES⁺]: m/z 1069.56 [M+H]⁺; Retention time (min): 1.44; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 9.93 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.38–7.32 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.61 (t, J = 8.4 Hz, 1H), 6.62–6.59 (m, 3H), 5.66 (d, J = 7.6 Hz, 1H), 5.37–5.15 (m, 3H), 4.53–4.44 (m, 3H), 4.41–4.23 (m, 3H), 4.14–4.05 (m, 3H), 3.93 (bs, 2H), 3.60 (bs, 2H), 3.27 (bs, 1H), 3.13–3.02 (m, 5H), 2.85–2.71 (m, 2H), 2.65–2.54 (m, 4H), 2.43–2.32 (m, 6H), 2.16–1.95 (m, 5H), 1.88–1.66 (m, 6H), 1.56–1.29 (m, 2H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 125: Synthesis of 3-[4-[1-[2-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]acetyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 133): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro 123567 h h d li i 8 l] h ] ido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid)and 3-[4-[1-[2-(4-piperidyl)acetyl]-4-piperidyl]anilino]piperidine-2,6- dione (C-98) (44.26 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (63.70 mg, 492.86 μmol, 85.84 μL)followed by addition HATU (56.22 mg, 147.86 μmol)portion wise. The reaction mixture was stirred at 25 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[4-[1-[2-[1-[5-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]acetyl]-4- piperidyl]anilino]piperidine-2,6-dione (Compound 133) (26 mg, 22.18 μmol, 22.50% yield, 91.12% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*150*5μm); Mobile phase A: 10 mM Ammonium acetate in water (AQ); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/10, 10/45, 13/45; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1068.60 [M+H]⁺; Retention time (min): 5.48; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 9.92 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.4 Hz, 1H), 7.38–7.31 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 6.56 (s, 1H), 5.66 (d, J = 7.6 Hz, 1H), 5.37–5.14 (m, 3H), 4.12–4.33 (m, 6H), 4.31–4.23 (m, 2H), 4.17–3.95 (m, 3H), 3.12–3.01 (m, 5H), 2.86–2.67 (m, 3H), 2.61–2.53 (m, 4H), 2.41–2.26 (m, 4H), 2.13–1.94 (m, 6H), 1.89–1.66 (m, 8H), 1.47–1.28 (m, 2H), 1.12 (bs, 2H), 0.70 (t, J = 7.6 Hz, 3H). Synthesis 126: Synthesis of 3-[4-[1-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-

d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperidine- 4-carbonyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 134): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL) was added DIPEA (38.22 mg, 295.71 μmol, 51.51 μL) and HATU (56.22 mg, 147.86 μmol) at 0 °C. After 5 minutes 3-[4-[1- (piperidine-4-carbonyl)-4-piperidyl]anilino]piperidine-2,6-dione (C-96) (42.87 mg, 98.57 μmol, hydrochloric acid) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 hours. The progress of reaction was monitored by TLC and LCMS. After completion, ice- cold water (3 mL) was added to the reaction mixture and lyophilized to afford crude product. The crude product was purified by Prep-HPLC to obtain the product 3-[4-[1-[1-[5-[7-(8-ethyl- 7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperidine-4-carbonyl]-4- piperidyl]anilino]piperidine-2,6-dione (Compound 134) (17 mg, 15.57 μmol, 15.80% yield, 96.56% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-SELECT C18 (19*150*5μm); Mobile phase A: 10mM Ammonium acetate in water (aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/15, 10/50, 12/50; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS [ES⁺]: 1054.58 [M+H]+; Retention time (min):1.59; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 10.26–9.84 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.38–7.32 (m, 2H), 7.02–6.93 (m, 3H), 6.60 (d, J = 10.0 Hz, 3H), 5.67 (d, J = 7.2 Hz, 1H), 5.35–5.14 (m, 3H), 4.68–4.23 (m, 8H), 4.14–4.03 (m, 3H), 3.17– 2.95 (m, 6H), 2.88–2.66 (m, 3H), 2.62–2.55 (m, 3H), 2.42–2.29 (m, 3H), 2.16–1.94 (m, 5H), 1.86–1.59 (m, 11H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 127: Synthesis of N-[5-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]pentyl]-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-N- methyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 135):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 103.91 μmol)and 3-[4-[1-[5-(methylamino)pentyl]-4-piperidyl]anilino]piperidine-2,6-dione (C-106) (40.16 mg, 103.91 μmol) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (40.29 mg, 311.72 μmol, 54.30 μL)followed by addition HATU (59.26 mg, 155.86 μmol) The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtain crude product. The crude product was purified by Prep-HPLC to afford product N-[5-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]pentyl]-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-N-methyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 135) (12.5 mg, 10.66 μmol, 10.26% yield, 88.87% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*250)5μ; Mobile phase A: 10 mM Ammonium acetate in water; Mobile phase B: 0.1% FA in acetonitrile; Gradient (Time/%B): 0/5, 2/5, 14/55; Flow rate: 18 mL/min; Solubility: Acetonitrile+ THF; LCMS [ES⁺]: m/z 1042.69 [M+H]⁺; Retention time (min): 5.85; ¹H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (m, 1H), 7.37–7.32 (m, 2H), 7.00 (s, 1H), 6.92 (t, J = 8.8 Hz, 1H), 6.59 (d, J = 5.6 Hz, 1H), 5.64– 5.62 (m, 1H), 5.36–5.11 (m, 3H), 4.52 (bs, 2H), 4.39–4.21 (m, 3H), 4.20–4.05 (m, 2H), 3.70– 3.54 (bs, 2H), 3.32 (bs, 2H), 3.18–2.90 (m, 8H), 2.88–2.63 (m, 3H), 2.60–2.52 (bs, 1H), 2.41– 2.25 (bs, 5H), 2.19–1.72 (m, 12H), 1.68–1.42 (m, 8H), 1.38–1.08 (m, 3H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 128: Synthesis of N-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]propyl]-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-

fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-N- methyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 136): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 Mg, 98.57 μmol, hydrochloric acid) and 3-[4-[1-[3-(methylamino)propyl]-4-piperidyl]anilino]piperidine- 2,6-dione (C-103) (31.14 mg, 78.86 μmol, hydrochloric acid) in N,N-dimethylformamide (2 mL) at 0 °C was added HATU (56.22 mg, 147.86 μmol) followed by addition DIPEA (38.22 mg, 295.71 μmol, 51.51 μL) The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtain crude product. The crude product was purified by Prep-HPLC to afford the product N-[3-[4-[4- [(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]propyl]-5-[7-(8-ethyl-7-fluoro-3-hydroxy- 1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-N-methyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (Compound 136) (21 mg, 20.17 μmol, 20.46% yield, 97.41% purity) as an off-white solid Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A: 10 mM Ammonium acetate in water (AQ); Mobile phase B: 0.1% FA in acetonitrile; Gradient (Time/%B): 0/5, 2/5, 14/55; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS [ES⁺]: m/z 1014.60 [M+H]⁺; Retention time (min): 1.44; ¹H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (m, 1H), 7.37–7.32 (m, 2H), 7.00 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.60–6.57 (m, 3H), 5.62 (t, J = 5.6 Hz, 1H), 5.36–5.11 (m, 3H), 4.52 (bs, 2H), 4.39–4.21 (m, 3H), 4.20–4.05 (m, 2H), 3.70– 3.54 (bs, 2H), 3.32 (bs, 2H), 3.18–2.90 (m, 5H), 2.88–2.63 (m, 4H), 2.60–2.52 (bs, 1H), 2.41– 2.25 (bs, 5H), 2.19–1.89 (m, 7H), 1.88–1.42 (m, 11H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 129: Synthesis of 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]ethyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 137): To stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[15-a][14]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) and 3-[4-[1-(2-piperazin-1-ylethyl)-4-piperidyl]anilino]piperidine-2,6- dione (C-89) (34.38 mg, 78.86 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL) at room temperature was added HATU (56.22 mg, 147.86 μmol) followed by DIPEA (38.22 mg, 295.71 μmol, 51.51 μL). The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC and LCMS. To the reaction mixture was added water (1 mL) solid was precipitated. A solid was filtered to afford crude product. The crude product was purified by Prep-HPLC to obtain product 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]ethyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 137) (23 mg, 19.40 μmol, 19.68% yield, 89.01% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A: 10mM Ammonium acetate in water (AQ); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B):0/10, 2/10, 15/100; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS [ES⁺]: m/z 1055.46 [M+H]⁺; Retention time (min): 1.37; ¹H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (m, 1H), 7.37–7.32 (m, 2H), 7.00 (s, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 8.8 Hz, 3H), 5.64 (d, J = 5.6 Hz, 1H), 5.37–5.16 (m, 3H), 4.52 (bs, 2H), 4.39–4.21 (m, 3H), 4.19–4.05 (m, 2H), 3.85 (bs, 2H), 3.54 (bs, 2H), 3.13–2.91 (m, 5H), 2.85–2.52 (m, 3H), 2.38– 2.32 (bs, 10H), 2.15–1.88 (m, 6H), 1.86–1.73 (m, 8H), 1.58–1.47 (bs, 4H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 130: Synthesis of N-[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]butyl]-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-N- methyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 138):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (80 mg, 112.65 μmol, hydrochloric acid) and 3-[4-[1-[4-(methylamino)butyl]-4-piperidyl]anilino]piperidine- 2,6-dione (C-104) (33.57 mg, 82.09 μmol, hydrochloric acid) in N,N-dimethylformamide (1.00 mL) at 0 °C was added DIPEA (43.68 mg, 337.96 μmol, 58.87 μL) followed by addition of HATU (64.25 mg, 168.98 μmol) portion wise. The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product N-[4-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]butyl]-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-N-methyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 138) (15 mg, 13.53 μmol, 12.01% yield, 96.90% purity, formic acid) as an off- white solid. Prep-HPLC condition: Column: X-BRIDGE C18, 5 μm (250 mm x 19 mm); Mobile Phase A: 10 mM Ammonium acetate in water, B: ACN; Gradient (T%B): 0/10, 2/10, 15/100; Flow Rate: 18 mL/min; Sample Diluent: ACN+Water+THF; LCMS (ES⁺): m/z 1029.05 [M+H]⁺; Retention time (min): 2.91; ¹H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 9.19 (s, 1H), 7.78– 7.74 (m, 1H), 7.37–7.32 (m, 2H), 7.00 (s, 1H), 6.94–6.88 (m, 2H), 6.59–6.56 (m, 3H), 5.64 (d, J = 5.6 Hz, 1H), 5.37–5.16 (m, 3H), 4.52 (bs, 2H), 4.39–4.21 (m, 4H), 4.19–4.05 (m, 2H), 3.68 (bs, 1H), 3.28 (bs, 3H), 3.13–2.91 (m, 5H), 2.85–2.52 (m, 5H), 2.38–2.32 (bs, 2H), 2.18–1.72 (m, 14H), 1.68–1.40 (m, 6H), 1.38–1.27 (bs, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 131: Synthesis of 3-[4-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 139): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid)and 3-[4-[1-(4-piperidylmethyl)-4-piperidyl]anilino]piperidine-2,6- dione (C-48) (41.50 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (63.70 mg, 492.86 μmol, 85.84 μL) followed by addition HATU (56.22 mg, 147.86 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[4-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-4-piperidyl]methyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 139) (11 mg, 10.14 μmol, 10.28% yield, 95.86% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*150*5μm); Mobile phase A: 10 mM Ammonium acetate in water (AQ); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/10, 10/45, 13/45; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF. LCMS (ES⁺): m/z 1040.60 [M+H]⁺ _; Retention time (min): 1.44; ¹H NMR (400 MHz, DMSO-d6): 10.76 (s, 1H), 9.93 (s, 1H), 9.20 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.38–7.32 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.62–6.55 (m, 3H), 5.65 (d, J = 7.6 Hz, 1H), 5.38–5.14 (m, 3H), 4.64–4.42 (m, 4H), 4.40–4.23 (m, 3H), 4.17–4.06 (m, 2H), 3.14–2.80 (m, 8H), 2.77–2.66 (m, 2H), 2.62–2.53 (m, 3H), 2.41–1.90 (m, 4H), 2.16–1.95 (m, 7H), 1.90–1.55 (m, 11H), 0.71 (t, J = 7.6 Hz, 3H). Synthesis 132: Synthesis of 3-[4-[1-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine- 1-carbonyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 140):

To stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) and 3-[4-[1-(piperazine-1-carbonyl)-4-piperidyl]anilino]piperidine- 2,6-dione (C-92) (42.97 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1 mL) at room temperature was added HATU (56.22 mg, 147.86 μmol) followed by DIPEA (63.70 mg, 492.86 μmol, 85.85 μL). The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC and LCMS. To the reaction mixture was added water (1 mL) solid was precipitated. A solid was filtered to afford crude product. The crude product was purified by Prep-HPLC to obtain product 3-[4-[1-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazine-1-carbonyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 140) (26 mg, 23.66 μmol, 24.00% yield, 96% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A: 10 mM Ammonium acetate in water (aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/10, 15/100; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF. LCMS [ES⁺]: m/z 1055.69 [M+H]⁺; Retention time (min): 1.59; ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 10.08 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (m, 1H), 7.37–7.32 (m, 2H), 7.00 (s, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.64 (s, 1H), 6.60 (d, J = 8.4 Hz, 2H), 5.66 (d, J = 7.6 Hz, 1H), 5.39–5.13 (m, 3H), 4.52 (bs, 2H), 4.39–4.21 (m, 3H), 4.19–4.05 (m, 2H), 3.95 (bs, 2H), 3.72 (d; J = 6.8 Hz, 2H), 3.60 (bs, 2H), 3.27 (s, 4H), 3.13–2.97 (m, 3H), 2.88–2.62 (m, 3H), 2.51 (bs, 2H), 2.42–2.31 (bs, 3H), 2.16–1.93 (m, 5H), 1.88–1.63 (m, 6H), 1.58–1.46 (m, 2H), 0.71 (t, J = 7.4 Hz, 3H). Synthesis 132: Synthesis of 3-[4-[1-[2-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]ethyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 141): To stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (50 mg, 70.41 μmol, hydrochloric acid) and 3-[4-[1-[2-(4-piperidyl)ethyl]-4-piperidyl]anilino]piperidine-2,6- dione (C-75) (30.63 mg, 70.41 μmol, hydrochloric acid) in N,N-dimethylformamide (1 mL) at room temperature was added HATU (40.16 mg, 105.61 μmol) followed by DIPEA (45.50 mg, 352.04 μmol, 61.32 μL). The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC and LCMS. To the reaction mixture was added water (1 mL) solid was precipitated. A solid was filtered to afford crude product. The crude product was purified by Prep-HPLC to obtain product 3-[4-[1-[2-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-4-piperidyl]ethyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 141) (21 mg, 18.23 μmol, 25.89% yield, 91.50% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A: 10 mM Ammonium acetate in water (aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/10, 15/100; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF. LCMS [ES⁺]: m/z 1054.62 [M+H]⁺; Retention time (min): 5.86; ¹H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (m, 1H), 7.37–7.32 (m, 2H), 7.00 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 6.56 (s, 1H), 5.63 (d, J = 5.6 Hz, 1H), 5.37–5.16 (m, 3H), 4.61–4.22 (m, 7H), 4.19– 4.05 (m, 2H), 3.13–2.88 (m, 6H), 2.85–2.52 (m, 3H), 2.38–2.22 (bs, 5H), 2.15–1.95 (m, 5H), 1.88–1.50 (m, 16H), 1.41 (bs, 2H), 1.07 (bs, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 133: Synthesis of N-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]ethyl]-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-N- methyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 142):

To stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) and 3-[4-[1-[2-(methylamino)ethyl]-4-piperidyl]anilino]piperidine- 2,6-dione (C-102) (37.55 mg, 98.57 μmol, hydrochloric acid) in N,N-dimethylformamide (1 mL) at room temperature was added HATU (56.22 mg, 147.86 μmol) followed by DIPEA (63.70 mg, 492.86 μmol, 85.85 μL). The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC and LCMS. To the reaction mixture was added water (1 mL) solid was precipitated. A solid was filtered to afford crude product. The crude product was purified by Prep-HPLC to obtain product N-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]ethyl]-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-N-methyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 142) (14 mg, 11.75 μmol, 11.92% yield, 83.96% purity) as an off-white solid. Prep-HPLC condition: Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A: 10 mM Ammonium acetate in water (aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B):0/10, 2/10,15/100; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF. LCMS [ES⁺]: m/z 1000.58 [M+H]⁺; Retention time (min): 5.61.¹H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (m, 1H), 7.37–7.32 (m, 2H), 7.00 (s, 1H), 6.94–6.88 (m, 2H), 6.59–6.53 (m, 3H), 5.64 (d, J = 5.6 Hz, 1H), 5.37–5.16 (m, 3H), 4.52 (bs, 2H), 4.39–4.21 (m, 4H), 4.19–4.05 (m, 2H), 3.68 (bs, 1H), 3.52 (bs, 1H), 3.33 (bs, 1H), 3.13–2.91 (m, 6H), 2.88–2.54 (m, 4H), 2.45 (bs, 1H), 2.42–2.27 (bs, 3H), 2.14–1.72 (m, 12H), 1.69–1.36 (m, 5H), 0.71 (t, J = 7.2 Hz, 3H). The following degraders are prepared using the method described above in Compound 142 synthesis, with the corresponding amine. Compound Compound Structure Compound 173 Compound 174 Compound 175

O N Compound N N N N F N O 176 N N ^O _H Et N N N N F O HO N F Compound 177 Compound 178 Compound 179 Compound 180 Synthesis 134: Synthesis of 3-[5-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[1-(pyrrolidin-1-ylmethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]- 4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 181):

Step-1: To a stirred solution of [1-(pyrrolidin-1-ylmethyl)cyclopropyl]methanol (1) (155.38 mg, 1.00 mmol) in THF (8 mL) was cool to 0 ^oC and added NaH ^60% dispersion in oil ^ (40.03 mg, 1.67 mmol) under argon atmosphere. After 5 minute, benzyl 4-[5-(2,7-dichloro-8-fluoro- pyrido[4,3-d]pyrimidin-4-yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazine-1-carboxylate (A-8) (400 mg, 667.29 μmol) was added, and the reaction mixture was allowed to attain room temperature. The reaction mixture was stirred at room temperature for 4 hours, while monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was filtered through celite 10% methanol/ dichloromethane (2 x 20 mL), then filtrate was extracted into 10% methanol/ dichloromethane (2 X 20 mL). The collected organic layer was washed with saturated brine solution (10 mL). The organic layer was dried over with anhydrous Na₂SO₄, filtered and then concentrated to afford the crude product. Then crude product was purified by column chromatography using silica gel (100-200 mesh), desired product was eluted at 1.5% methanol/ dichloromethane to afford benzyl 4-[5-[7-chloro- 8-fluoro-2-[[1-(pyrrolidin-1-ylmethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (2) (240 mg, 210.59 μmol, 31.56% yield, 63.02% purity) as a brown gummy. LCMS (ES⁺): m/z 718.74 [M+H]⁺; Retention time (min): 0.68. Step-2: To a solution of benzyl 4-[5-[7-chloro-8-fluoro-2-[[1-(pyrrolidin-1- ylmethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (2) (240 mg, 334.16 μmol) and 2-[8- ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3) (180.56 mg, 501.24 μmol) in mixture of water (0.4 mL) and tetrahydrofuran (4 mL) was added potassium phosphate tribasic (141.86 mg, 668.32 μmol) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes then cataCXium-A-Pd-G3 (24.34 mg, 33.42 μmol) was added. The resulting reaction mixture was stirred at 100 °C for an hour in a microwave apparatus. The progress of the reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was filtered through celite using ethyl acetate (2 x 50 mL), then filtrate was extracted into 10% methanol/ dichloromethane (2 x 50 mL). The collected organic layer was washed with saturated brine solution (20 mL). The organic layer was dried over with anhydrous Na2SO4, filtered and then concentrated. Thus the obtained crude product was purified by silica gel (100-200 mesh) column chromatography by eluting at 9% methanol/ dichloromethane to afford benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]- 8-fluoro-2-[[1-(pyrrolidin-1-ylmethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (4) (160 mg, 146.56 μmol, 43.86% yield, 83.91% purity) as a yellow solid. LCMS (ES⁺): m/z 916.84 [M+H]⁺; Retention time (min): 0.84. Step-3: To a solution of benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[1-(pyrrolidin-1-ylmethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (4) (180 mg, 196.50 μmol) in methanol (2 mL) and ethyl acetate (2 mL) was added 10% palladium on carbon wet (180 mg, 1.69 mmol) stirred reaction mixture at room temperature for two hours under hydrogen bladder pressure, while monitored by TLC and LCMS. After completion of starting material, the reaction mixture was filtered through celite bed and washed with methanol : ethyl acetate (1:1, 20 mL x 3), concentrated under reduced pressure to afford [5-[7-[8-ethyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-(pyrrolidin-1- ylmethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (5) (200 mg, 181.41 μmol, 92.32% yield, 70.92% purity) as a brown solid. LCMS (ES⁺): m/z 782.87 [M+H]⁺; Retention time (min): 0.58. Step-4: To a stirred solution of [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[1-(pyrrolidin-1-ylmethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (5) (200 mg, 255.79 μmol) in dichloromethane (2 mL) was added HCl (4.0 M in 1,4-dioxane) (9.33 mg, 255.79 μmol, 0.8 mL) at 0 °C. Then the resulting reaction mixture was stirred at room temperature for two hours. The progress of reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure to afford crude product. which was triturated with diethyl ether (10 mL x 3) to afford [5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[1-(pyrrolidin-1-ylmethyl)cyclopropyl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl- methanone (6) (0.180 g, 197.53 μmol, 77.22% yield, 84.97% purity, hydrochloric acid) as a yellow solid. LCMS (ES⁺): m/z 738.48 [M+H]⁺; Retention time (min): 1.34. Step-5: To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1- (pyrrolidin-1-ylmethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (6) (0.170 g, 219.55 μmol, hydrochloric acid) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]acetic acid (C-21) (90.36 mg, 175.64 μmol, trifluoroacetic acid) in N,N- dimethylformamide (2.01 mL) at 0 °C was added HATU (125.22 mg, 329.33 μmol) followed by addition DIPEA (141.88 mg, 1.10 mmol, 191.21 μL). The reaction mixture was stirred at 25 °C for 12 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[1-[2-[4- [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1-(pyrrolidin-1- ylmethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione (Compound 181) (17 mg, 14.18 μmol, 6.46% yield, 93.43% purity) as an off-white solid. Column/dimensions: X-BRIDGE C18 (19*150*5μm); Mobile phase A: 10 mM Ammonium acetate in water (aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/102/1010/4513/45; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1120.61 [M+H]⁺; Retention time (min): 1.44; ¹H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.94 (s, 1H), 9.18 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.4 Hz, 1H), 7.37–7.32 (m, 2H), 7.07 (s, 1H), 7.02–6.98 (m, 2H), 6.87–6.84 (m, 1H), 6.67 (s, 1H), 5.33–5.20 (m, 3H), 4.53 (d, J = 3.9 Hz, 2H), 4.41–4.25 (m, 4H), 4.06–3.93 (m, 2H), 3.68– 3.47 (bs, 6H), 3.31 (bs, 3H), 3.19 (bs, 2H), 2.97–2.83 (m, 3H), 2.73–2.55 (m, 2H), 2.44–2.29 (m, 10H), 2.11 (t, J = 10.0 Hz, 3H), 2.03–1.96 (m, 1H), 1.89 (bs, 1H), 1.77–1.58 (m, 7H), 0.71 (t, J = 7.2 Hz, 3H), 0.61 (d, J = 6.2 Hz, 2H), 0.42 (d, J = 5.8 Hz, 2H). Synthesis 135: Synthesis of 3-[5-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[1-[[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5- yl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4- piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 182):

Step-1: A stirred solution of [1-[[(4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5- yl]methyl]cyclopropyl]methanol (1) (183.42 mg, 1.00 mmol) in tetrahydrofuran (8 mL) was cooled to 0 ^oC and then NaH ^60% dispersion in oil ^ (40.03 mg, 1.67 mmol) was added under argon atmosphere. After 5 minutes, benzyl 4-[5-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin- 4-yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (A- 8) (400 mg, 667.29 μmol) was added, and allowed reaction mixture to attain room temperature. The reaction mixture was stirred at room temperature for 3 hours, while monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was filtered through celite 10% methanol/ dichloromethane (2 x 20 mL), then filtrate was extracted into 10% methanol/ dichloromethane (2 x 20 mL). The collected organic layer was washed with saturated brine solution (10 mL). The organic layer was dried over with anhydrous Na2SO4, filtered and then concentrated to afford the crude product. Then crude product was purified by column chromatography using silica gel (100-200 mesh), desired product was eluted at 1% methanol/ dichloromethane to afford benzyl 4-[5-[7-chloro-8-fluoro-2-[[1-[[(4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (2) (225 mg, 238.92 μmol, 35.80% yield, 79.24% purity) as a brown gummy. LCMS (ES⁺): m/z 747.16 [M+H]⁺ _; Retention time (min): 0.67. Step-2: To a solution of benzyl 4-[5-[7-chloro-8-fluoro-2-[[1-[[(4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (2) (225 mg, 301.52 μmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (3) (108.61 mg, 301.52 μmol) in a mixture of water (0.4 mL) and tetrahydrofuran (4 mL) was added potassium phosphate tribasic (128.00 mg, 603.03 μmol) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes then added cataCXium-A-Pd-G3 (21.96 mg, 30.15 μmol), the resulting reaction mixture was stirred at 100 °C for an hour in a microwave apparatus. The progress of the reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was filtered through celite using ethyl acetate (2 X 50 mL), then filtrate was extracted into 10% methanol/ dichloromethane (2 X 50 mL). The collected organic layer was washed with saturated brine solution (20 mL). The organic layer was dried over with anhydrous Na2SO4, filtered and then concentrated. Thus the obtained crude product was purified by silica gel (100 -200 mesh) column chromatography by eluting at 3% methanol/ dichloromethane to afford benzyl 4-[5-[7-[8-ethyl- 7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1-[[(4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (4) (170 mg, 153.07 μmol, 50.77% yield, 85% purity) as a yellow solid. LCMS (ES⁺): m/z 944.84 [M+H]⁺; Retention time (min): 0.85. Step-3: To a solution of benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[1-[[(4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5- yl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (4) (200 mg, 211.86 μmol) in methanol (2 mL) and ethyl acetate (2 mL) was added 10% palladium on carbon wet (200 mg, 1.88 mmol) stirred reaction mixture at room temperature for two hours under hydrogen bladder pressure, while monitored by TLC and LCMS. After completion of starting material, the reaction mixture was filtered through celite bed and washed with methanol : ethyl acetate (1:1, 20 mL x 3), concentrated under reduced pressure to afford [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[1-[[(4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5- yl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (5) (150 mg, 158.28 μmol, 74.71% yield, 85.46% purity) as a light brown solid. LCMS (ES⁺): m/z 810.78 [M+H]⁺; Retention time (min): 2.31. Step-4: To the stirred solution of [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[1-[[(4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5- yl]methyl]cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (5) (150 mg, 185.21 μmol) in dichloromethane (2 mL) was added HCl (4.0 M in 1,4-dioxane) (6.75 mg, 185.21 μmol, 0.15 mL) at 0 °C and the resulting reaction mixture was stirred for 15 minutes at 0 °C. The reaction progress was monitored by TLC and LCMS. The reaction mixture was concentrated under reduced pressure to obtain crude compound. The crude product was triturated in diethyl ether (2 x 5 mL) and dried under reduced pressure to afford [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1- [[(4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methyl]cyclopropyl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl- methanone (6) (140 mg, 127.50 μmol, 68.84% yield, 73.07% purity, hydrochloric acid) as a yellow solid. LCMS (ES⁺): m/z 766.34 [M+H]⁺; Retention time (min): 2.93. Step-5: To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1- [[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methyl]cyclopropyl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl- methanone (6) (130.00 mg, 162.03 μmol, hydrochloric acid) and 2-[4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetic acid (C-21) (66.69 mg, 129.63 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) at 0 °C was added HATU (92.41 mg, 243.05 μmol) followed by addition of DIPEA (104.71 mg, 810.16 μmol, 141.11 μL). The reaction mixture was stirred at 25 °C for 16 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1- [[(1R,4R)-2-oxa-5-azabicyclo[221]heptan-5-yl]methyl]cyclopropyl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]- 2-oxo-ethyl]-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 182) (24 mg, 18.49 μmol, 11.41% yield, 88.48% purity) as an off-white solid. Column/dimensions: X-BRIDGE C18 (19*150*5μm); Mobile phase A: 10 mM Ammonium acetate in water (aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10,2/10,10/45,13/45; Flow rate: 18 mL/min; Solubility: Acetonitrile +Water+THF. LCMS (ES⁺): m/z 1148.66 [M+H]⁺; Retention time (min): 1.41. ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.93 (s, 1H), 9.18 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.07 (s, 1H), 7.02–6.98 (m, 2H), 6.93–6.87 (m, 1H), 6.66 (s, 1H), 5.35–5.16 (m, 3H), 4.53 (d, J = 5.6 Hz, 2H), 4.39–4.23 (m, 5H), 4.07–3.94 (m, 2H), 3.76 (d, J = 7.6 Hz, 1H), 3.69–3.54 (m, 4H), 3.52–3.45 (m, 4H), 3.31 (bs, 3H), 3.19 (bs, 2H), 2.97–2.82 (m, 4H), 2.73–2.54 (m, 5H), 2.46–2.33 (m, 6H), 2.17–1.96 (m, 4H), 1.78–1.48 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H), 0.58 (d, J = 6.2 Hz, 2H), 0.47 (d, J = 5.8 Hz, 2H). Synthesis 136: Synthesis of 3-[5-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]- 4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 183):

O O B Et O F N N N N Cbz MOMO 3 F N 10% Pd/C, H2, MeOH, K₃PO₄, CataCXium® A Pd G3, O Et EtOAc, RT, 2h THF, Water, 100°C, MW, 1h N N N Step-3 Step-2 N O F OMOM 4 Step-1: A stirred solution of [1-(morpholinomethyl)cyclopropyl]methanol (1) (171.40 mg, 1.00 mmol) in tetrahydrofuran (8 mL) was cooled to 0 ^oC and then NaH (60% dispersion in oil) (40.03 mg, 1.67 mmol) was added under argon atmosphere. After 5 minutes, benzyl 4-[5-(2,7-dichloro- 8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazine-1-carboxylate (A-8) (400 mg, 667.29 μmol) was added, and the reaction mixture was allowed to attain room temperature. The reaction mixture was stirred at room temperature for two hours, while monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was filtered through celite 10% methanol/ dichloromethane (2 x 10 mL), then filtrate was extracted into 10% methanol/ dichloromethane (2 x 10 mL). The collected organic layer was washed with saturated brine solution (5 mL). The organic layer was dried over with anhydrous Na2SO4, filtered and then concentrated to afford the crude product. Then crude product was purified by column chromatography using silica gel (100-200 mesh), desired product was eluted at 1% methanol/ dichloromethane to afford benzyl 4-[5-[7-chloro-8- fluoro-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (2) (240 mg, 269.97 μmol, 40.46% yield, 82.59% purity) as a brown gummy. LCMS (ES⁺): m/z 734.48 [M+H]⁺; Retention time (min): 0.70. Step-2: To a solution of benzyl 4-[5-[7-chloro-8-fluoro-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (2) (240 mg, 326.88 μmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (3) (176.63 mg, 490.32 μmol) in mixture of water (0.8 mL) and tetrahydrofuran (4 mL) was added potassium phosphate tribasic (138.77 mg, 653.76 μmol) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes then added cataCXium-A-Pd-G3 (23.81 mg, 32.69 μmol), The resulting reaction mixture was stirred at 100 °C for an hour in a microwave apparatus. The progress of the reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was filtered through celite using ethyl acetate (2 x 50 mL), then filtrate was extracted into 10% methanol/ dichloromethane (2 x 50 mL). The collected organic layer was washed with saturated brine solution (20 mL). The organic layer was dried over with anhydrous Na2SO4, filtered and then concentrated. Thus the obtained crude product was purified by silica gel (100 -200 mesh) column chromatography by eluting at 3% methanol/ dichloromethane to afford benzyl 4-[5-[7-[8-ethyl- 7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (4) (230 mg, 155.57 μmol, 47.59% yield, 63.04% purity) as a yellow solid. LCMS (ES⁺): m/z 932.78 [M+H]⁺; Retention time (min): 0.78. Step-3: To a solution of benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (4) (230 mg, 246.78 μmol) in methanol (2 mL)and ethyl acetate (2 mL) was added 10% palladium on carbon wet (230.00 mg, 2.16 mmol). The reaction mixture was stirred at room temperature for 6 hours under hydrogen bladder pressure, while monitored by TLC and LCMS. After completion of starting material, the reaction mixture was filtered through celite bed and washed with methanol: ethyl acetate (1:1, 20 mL x 3), concentrated under reduced pressure to afford [5-[7-[8-ethyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (5) (160 mg, 122.24 μmol, 49.54% yield, 60.96% purity) as a light green solid. LCMS (ES⁺): m/z 798.49 [M+H]⁺; Retention time (min): 1.44. Step-4: To a solution of [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[1-(morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (5) (230 mg, 288.26 μmol) in dichloromethane (0.5 mL) was added HCl (4.0 M in 1,4-dioxane) (31.53 mg, 864.78 μmol, 1 mL) at 0 °C and the reaction mixture was stirred at 0 °C for 15 minutes. The reaction mixture was concentrated in vacuo to afford the crude product, which was triturated with diethyl ether (2 x 3 mL) to afford [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (6) (170 mg, 110.85 μmol, 38.45% yield, 51.53% purity, hydrochloric acid) as a light yellow solid. LCMS (ES⁺): m/z 754.68 [M+H]⁺; Retention time (min): 0.51. Step-5: To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (6) (160 mg, 202.45 μmol, hydrochloric acid)and 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]acetic acid (C-21) (81.07 mg, 157.58 μmol, trifluoroacetic acid) in N,N- dimethylformamide (3 mL) at 0 °C was added DIPEA (130.83 mg, 1.01 mmol, 176.32 μL) followed by addition of HATU (115.47 mg, 303.68 μmol) portion wise. The reaction mixture was stirred at 25 °C for 3 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[1- [2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]- 3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 183) (13 mg, 10.62 μmol, 5.24% yield, 92.79% purity) as an off-white solid. Column/dimensions: X-SELECT C18 (19*250*5μm); Mobile phase A: 10 mM Ammonium acetate in water (aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10,2/20,10/60,13/60; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1136.65 [M+H]⁺; Retention time (min): 5.51; ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.95 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.07 (s, 1H), 7.02–6.98 (m, 2H), 6.91 (d, J = 6.4 Hz, 1H), 6.67 (s, 1H), 5.36–5.16 (m, 3H), 4.53 (d, J = 5.2 Hz, 1H), 4.38–4.26 (m, 4H), 4.07–3.92 (m, 2H), 3.68–3.45 (bs, 11H), 3.31 (bs, 3H), 3.19 (bs, 2H), 2.96–2.84 (m, 3H), 2.74–2.57 (m, 3H), 2.40–2.26 (m, 6H), 2.29 (bs, 2H), 2.11 (t, J = 10.0 Hz, 3H), 2.03–1.96 (m, 1H), 1.88 (bs, 1H), 1.77–1.63 (m, 4H), 0.71 (t, J = 7.6 Hz, 3H), 0.64 (d, J = 6.2 Hz, 2H), 0.41 (d, J = 5.8 Hz, 2H). Synthesis 137: Synthesis of 3-[5-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]- 4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 184):

Step-1: To a stirred solution of 3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)propan-1-ol (1) (171.40 mg, 1.00 mmol) in tetrahydrofuran (8 mL) was cool to 0 ^oC and added sodium hydride (in oil dispersion) 60% dispersion in mineral oil (40.03 mg, 1.67 mmol) under argon atmosphere. After 5 minutes, benzyl 4-[5-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (A-8) (400 mg, 667.29 μmol) was added, and the reaction mixture was allowed to attain room temperature. The reaction mixture was stirred at room temperature for 4 hours, while monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was diluted with ice-cold water (20 mL) and extracted into 10% methanol/ dichloromethane (2 x 50 mL). The collected organic layer was washed with saturated brine solution (10 mL). The organic layer was dried over with anhydrous Na₂SO₄, filtered and then concentrated to afford the crude product. Then crude product was purified by column chromatography using silica gel (100-200 mesh), desired product was eluted at 2% methanol/ dichloromethane to afford benzyl 4-[5-[7-chloro-8-fluoro- 2-[3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (2) (210 mg, 202.67 μmol, 30.37% yield, 70.86% purity) as a brown gummy. LCMS (ES⁺): m/z 734.65 [M+H]⁺; Retention time (min): 0.66. Step-2: To a solution of benzyl 4-[5-[7-chloro-8-fluoro-2-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8- yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazine-1-carboxylate (2) (210 mg, 286.02 μmol) and 2-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3) (154.55 mg, 429.03 μmol) in mixture of water (0.4 mL) and tetrahydrofuran (3.2 mL) was added potassium phosphate tribasic (121.42 mg, 572.04 μmol) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes then added cataCXium-A-Pd-G3 (20.83 mg, 28.60 μmol). The resulting reaction mixture was stirred at 100 °C for two hours in a microwave apparatus. The progress of the reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was filtered through celite using ethyl acetate (2 x 50 mL), then filtrate was extracted into 10% methanol/ dichloromethane (2 x 50 mL). The collected organic layer was washed with saturated brine solution (20 mL). The organic layer was dried over with anhydrous Na₂SO₄, filtered and then concentrated. Thus the obtained crude product was purified by silica gel (100-200 mesh) column chromatography by eluting at 6% methanol/ dichloromethane to afford benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]- 8-fluoro-2-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (4) (220 mg, 151.94 μmol, 53.12% yield, 64.37% purity) as a yellow solid. LCMS (ES⁺): m/z 932.58 [M+H]⁺; Retention time (min): 1.91. Step-3: To a solution of benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (4) (220 mg, 236.05 μmol) in methanol (2 mL)and ethyl acetate (2 mL) was added 10% palladium on carbon wet (220.00 mg, 2.07 mmol) stirred reaction mixture at room temperature for 5 hours under hydrogen bladder pressure, while monitored by TLC and LCMS. After completion of starting material, the reaction mixture was filtered through celite bed and washed with methanol : ethyl acetate (1:1, 20 mL x 3), concentrated under reduced pressure to afford [5-[7-[8-ethyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8- yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]- piperazin-1-yl-methanone (5) (160 mg, 122.42 μmol, 51.86% yield, 61.05% purity) as a light green solid. LCMS (ES⁺): m/z 798.62 [M+H]⁺; Retention time (min): 0.59. Step-4: To a solution of [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (5) (160 mg, 200.53 μmol) in dichloromethane (2 mL) was added HCl (4.0 M in 1,4-dioxane) (7.31 mg, 200.53 μmol, 0.6 mL) at 0 °C and the reaction mixture was stirred at 0 °C for 15 minutes. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was concentrated in vacuum to afford the crude product, which was triturated with diethyl ether (2 X 3 mL) to afford [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[3-(3-oxa-8-azabicyclo[3.2.1]octan- 8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2- yl]-piperazin-1-yl-methanone (6) (140 mg, 119.43 μmol, 59.56% yield, 67.42% purity, hydrochloric acid) as a light yellow solid. LCMS (ES⁺): m/z 754.70 [M+H]⁺; Retention time (min): 0.56. Step-5: To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[3-(3- oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (6) (140 mg, 177.15 μmol, hydrochloric acid) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]acetic acid (C-21) (72.91 mg, 141.72 μmol, trifluoroacetic acid) in N,N- dimethylformamide (2 mL) at 0 °C was added HATU (101.04 mg, 265.72 μmol) followed by addition of DIPEA (11447 mg 88574 μmol 15428 μL) portion wise. The reaction mixture was stirred at 25 °C for 3 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (5 mL) to afford precipitated solid. A solid was filtered to afford crude product. The crude product was purified by prep-HPLC to afford product 3-[5-[1- [2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[3-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]- 3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 184) (16 mg, 13.40 μmol, 7.56% yield, 95.14% purity) as an off-white solid. Column/dimensions: X-SELECT C18 (19*250*5μm); Mobile phase A: 10 mM Ammonium acetate in water (aq); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10,2/20,10/60,13/60; Flow rate: 18 mL/min; Solubility: Acetonitrile+Water+THF; LCMS (ES⁺): m/z 1136.53 [M+H]⁺; Retention time (min): 1.39; ¹H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.96 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.07 (s, 1H), 7.02–6.98 (m, 2H), 6.91 (d, J = 7.2 Hz, 1H), 6.68 (s, 1H), 5.36–5.17 (m, 3H), 4.53–4.46 (m, 3H), 4.40–4.25 (m, 2H), 4.06–3.92 (m, 2H), 3.67–3.48 (bs, 9H), 3.38–3.29 (m, 5H), 3.19 (bs, 2H), 3.04 (bs, 2H), 2.96–2.84 (m, 3H), 2.74– 2.57 (m, 3H), 2.41–2.32 (m, 4H), 2.16–1.95 (m, 4H), 1.87–1.79 (m, 5H), 1.76–1.64 (m, 6H), 0.71 (t, J = 7.2 Hz, 3H). The following degraders are prepared using the method described above in the synthesis of Compound 181 to Compound 184 with the corresponding alcohol/amine in Step-1 and the corresponding CRBN binder in Step-5. Compound # Compound Structure Compound 185

Compound 186 Compound 187 Compound 188 O N N N N N N O O F N N Et N N O (S) HN N O N O F O OH Compound 189

Compound 190 Compound 191 Compound 192 Compound 193

Compound 194 Compound 195 O N N H N N N _O ^N O O F N N Et H N N N O N F OH Compound 196 Compound 197

Compound 198 Compound 199 Compound 200 Compound 201

Compound 202 Compound 205 Compound 207 Compound 210

Compound 211 Compound 212 Compound 213 Compound 214

Compound 215 Compound 216 Compound 217 Compound 218

Compound 227 Compound 228 Compound 229 Compound 230

Compound 231 Compound 232 Compound 233 Compound 234

Compound 235 Compound 236 Compound 237 Compound 238

Compound 239 Compound 240 Compound 241 Compound 242

Compound 243 Compound 244 Compound 245 Compound 246

Compound 247 Compound 248 O N N H N N N _O ^N O O F N N Et H N N N O N F ^(R) O OH Compound 249 O N N H N N N _O ^N O O F N N Et H N N N O N F ^(S) O OH Compound 250

Compound 251 Compound 252 Compound 253 O N N H N N N _O ^N O O F N O N Et H N N N N O F OH Compound 254 O N N H N N N _O ^N O F O F N N Et H N N N N O F OH Compound 255 Compound 256 Compound 257 O N N H N N N _O ^N O O F N N Et H N N N O N F F O F OH Compound 258

Compound 259 O N N H N N N _O ^N O O F N N Et H N N (R) N O N F OH Compound 260 Compound 261 Compound 262

Compound 263 O N N H N N N _O ^N O O F N N Et H N N (R) N O N F O OH Compound 264 Compound 265 Compound 266

Compound 267 Compound 268 O N N H N N N _O ^N O O F N N Et H N N (R) N O N F O OH Compound 269 Compound 270

Compound 271 Synthesis 138: Synthesis of 3-(6-(1-((1-(5-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2- carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione (Compound 272)

Step-1: To a stirred solution of ethyl 5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (1) (1 equiv.) in tetrahydrofuran/ water (v/v = 6/1) are added 2-(8-ethylnaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2) (1- 3 equiv.) and potassium phosphate tribasic (3–5 equiv.). The mixture is degassed with argon for 5 minutes followed by addition of cataCXium® A Pd G3 (10 mol %) at room temperature. The reaction mixture is degassed again for 5 minutes and heated with stirring at 80 °C for 16 hours. Completion of the reaction is indicated by TLC and LCMS. Product formation is confirmed by LCMS. The reaction mixture is concentrated under reduced pressure and the crude is purified by flash column chromatography. The combined fractions are evaporated to afford ethyl 5-(7-(8- ethylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine- 2-carboxylate (3). Step-2: To a solution of ethyl 5-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (3) (1 equiv.) in tetrahydrofuran is added lithium hydroxide monohydride (1–2 equiv.) at 0 °C. The reaction mixture is stirred at room temperature for 4 hours. The progress of reaction is monitored by TLC and LCMS, product formation is confirmed by TLC. After the consumption of the starting material, solvent is evaporated and the crude compound is purified by reverse phase column chromatography to afford 5-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxylic acid (4). Step-3: To a stirred solution of 5-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (4) (1 equiv.) and 3-(1-methyl- 6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (C-49) (1-2 equiv.) in N,N-dimethylformamide at 0 °C is added DIPEA (5-10 equiv.) followed by addition of HATU (1–3 equiv.). The reaction mixture is stirred at 25 °C until the reaction is complete. The reaction mixture is diluted with cold water to afford a precipitate, which is filtered to afford the crude product. The crude product is purified by prep-HPLC to afford 3-(6-(1-((1-(5-(7-(8- ethylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (Compound 272). The following degraders are prepared using the method described above in Compound 272 synthesis, with the corresponding boronic ester in Step-1. Compound Boronic Ester Compound Structure Compound 273 Compound 274 Compound 275 Compound 276 Compound 277 Synthesis 139: Synthesis of 3-(6-(1-((1-(5-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-

carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione (Compound 278) Step-1: To a stirred solution of ethyl 5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (1) (1 equiv.) in tetrahydrofuran / water (v/v = 6/1) are added 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (2) (1-3 equiv.) and potassium phosphate tribasic (3–5 equiv.). The mixture is degassed with argon for 5 minutes followed by addition of cataCXium® A Pd G3 (10 mol %) at room temperature. The resulting mixture is degassed again for 5 minutes and heated with stirring at 80 °C for 16 hours. Completion of the reaction is indicated by TLC and LCMS. Product formation is confirmed by LCMS. The reaction mixture is concentrated under reduced pressure and the crude is purified by flash column chromatography. The combined fractions are evaporated to afford ethyl 5-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (3). Step-2: To a solution of ethyl 5-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (3) (1 equiv.) in tetrahydrofuran is added lithium hydroxide monohydride (1–2 equiv.) at 0 °C. The reaction mixture is stirred at room temperature for 4 hours. The progress of reaction is monitored by TLC and LCMS, product formation is confirmed by TLC. After the consumption of the starting material, solvent is evaporated and the crude compound is purified by reverse phase column chromatography to afford 5-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (4). Step-3: To a stirred solution of 5-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (5) in dichloromethane at 0 °C is added HCl (4.0 M in 1,4-dioxane) (1–5 equiv.) and stirred for 5 minutes at the same temperature and then stirred at 25 °C until the reaction is complete. The reaction mixture is concentrated under reduced pressure and the obtained crude product is subjected to standard workup condition to afford 5-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (5). Step-4: To a stirred solution of 5-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (5) (1 equiv.) and 3-(1-methyl- 6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (C-49) (1-2 equiv.) in N,N-dimethylformamide at 0 °C is added DIPEA (5 -10 equiv.) followed by addition of HATU (1–3 equiv.). The reaction mixture is stirred at 25 °C until the reaction is complete. The reaction mixtu i dil d i h ld ff d i i which is filtered to give the crude product. The crude compound was purified by prep-HPLC to afford 3-(6-(1-((1-(5-(7- (8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (Compound 278). The following degraders are prepared using the method described above in Compound 278 synthesis, with the corresponding boronic ester in Step-1. Compound Boronic Acid/Ester Compound Structure Compound 279 Compound 280 Compound 282 Compound 283 Compound 284 Compound 285 Compound 286

Compound 287 Compound 288 Compound 289 N ^N O NH O O N N N N Compound 290 N N N N HN N O N F Cl F _N ^N O NH O O N N N Compound N 291 N N N N HN N O N F Me Cl F Compound 292 BocHN Compound N HO S B OH 293 F Compound 294 Compound 295 Synthesis 140: Synthesis of 3-[6-[1-[[1-[5-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 296):

Step-1: To a stirred solution of ethyl 5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 1 (200 mg, 364.97 μmol) and 2-[2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- naphthyl]ethynyl-triisopropyl-silane 2 (374.12 mg, 729.95 μmol) in a mixture of tetrahydrofuran (1.6 mL) and water (0.2 mL) was added K₃PO₄ (232.42 mg, 1.09 mmol). The reaction mixture was degassed with argon for 5 minutes. Catacxium Pd G3 (53.16 mg, 72.99 μmol) was added and the reaction mixture was heated to stirred at 100 °C for 2 hours in microwave. The reaction mixture was concentrated under reduced pressure to afford crude compound which was purified by flash column chromatography (100-200 silica) using 3-5% methanol in dichloromethane as an eluent to afford ethyl 5-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1- naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxylate 3 (250 mg, 46% yield) as a brown thick liquid. LCMS (ESI): m/z 898.87[M+H]⁺. Step-2: To a stirred solution of ethyl 5-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilyl- ethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylate 3 (200 mg, 222.69 μmol) in a mixture of tetrahydrofuran (1 mL), methanol (1 mL) and water (0.5 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to get the crude compound which was purified by reverse phase column chromatography using C18 cartridge, eluted with 0.1% ammonium bicarbonate in water and acetonitrile to afford 5-[8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 4 (100 mg, 43 % yield) as a brown solid. LCMS (ESI): m/z 870.86 [M+H]⁺. Step-3: To a stirred solution of 5-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 4 (100 mg, 114.94 μmol) in N,N- dimethylformamide (1 mL) was added cesium fluoride (87.30 mg, 574.68 μmol) at 0 °C. The resulting reaction mixture was allowed to stir at room temperature for 3 hours. The reaction mixture diluted with water and extracted with 10% methanol in dichloromethane (50 mL), The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to afford 5-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 5 (100 mg, 79% yield) as thick yellow liquid. LCMS (ESI): m/z 714.86 [M+H]⁺. Step-4: To the stirred solution of 5-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 5 (100 mg, 140.11 μmol) in dichloromethane (1 mL) was added 4 M HCl ( 0.2 mL) in 1,4-dioxane at 0 °C. The resulting reaction mixture was allowed to stir at room temperature for an hour. The reaction mixture was concentrated under reduced pressure to get crude which was triturated with diethyl ether to afford 5-[ ( h l fl h d h h l) fl oro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 6 (70 mg, 62 % yield, hydrochloric acid salt) as a grey solid. LCMS (ESI): m/z 670.75 [M+H]⁺. Step-5: To a stirred solution of 5-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 6 (60 mg, 84.97 μmol, hydrochloric acid salt) and 3-[1-methyl-6-[1-(4-piperidylmethyl)-4-piperidyl]indazol-3- yl]piperidine-2,6-dione 7 (31.27 mg, 67.98 μmol, hydrochloric acid salt) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (32.95 mg, 254.92 μmol) followed by addition of HATU (48.46 mg, 127.46 μmol). The resulting reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was lyophilized to get crude which was purified by SFC-Prep method to afford 3-[6-[1-[[1-[5-[7-(8-ethynyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-4-piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 296 (9 mg, 9% yield, trifluoroacetic acid salt) as a yellow solid. LCMS (ESI): m/z 1075.86 [M+H]⁺. SFC-Prep method: [Column/dimensions: Ethyl pyridine (30 x 250) mm,5μ, % CO₂: 65%, % Co solvent: 35% (0.2% 7N methanolic ammonia in CH₃CN: methanol) (1:1), Flow: 100mL/min, Back Pressure: 100 bar, Temperature: 30 °C, UV: 220 nm, Solubility: methanol, No. of injections: 6, Total purification time: 01:00 hour, Run time per injection: 7 min].¹H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1H), 10.20 (bs, 1H), 9.19 (s, 1H), 8.01–7.97 (m, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.49–7.45 (m, 1H), 7.40 (d, J = 2.8 Hz, 2H), 7.21 (s, 1H), 7.17 (d, J = 2.4 Hz, 1H), 6.70 (s, 1H), 5.75–5.09 (m, 3H), 4.89–4.49 (m, 5H), 4.42–4.18 (m, 4H), 4.09–3.75 (m, 4H), 3.70–3.52 (m, 3H), 3.31–3.29 (m, 3H), 3.22–3.09 (m, 3H), 3.0–3.91 (m, 3H), 2.85–2.71 (m, 2H), 2.63–2.53 (m, 5H), 2.48–2.39 (m, 2H), 2.28–2.15 (m, 4H), 2.12–2.01 (m, 3H), 1.92–1.73 (m, 2H), 1.25–1.22 (m, 2H), 1.17–1.13 (m, 2H) ppm. The following degrader is prepared using the method described above in Compound 296 synthesis, with the corresponding boronic ester in Step-1. Compound Boronic Ester Compound Structure Compound 297 The following degraders are prepared using the method described above in Compound 296 synthesis with the corresponding carboxylic acid in Step-5. ^Compound Carboxylic Acid Compound Structure Compound 300 Compound 301

Compound 302 Compound 303 Compound 304

Compound 305 Compound 306 Compound 307

Compound 308 Compound 309 Compound 310 Compound 311 O N OH N Compound F OMe N 312 Et N N N O N F OH F O N OH N Compound F OEt N 313 Et N N N O N F OH F O N OH N Compound F O N 314 Et N N N O N F OH F

O N OH N Compound F O N 315 Et N N N O N F OH F O N OH N Compound F O N 316 Et N N N O N F OH F O N OH N Compound F N 317 Et N N O N F OH F Synthesis 141: Synthesis of 3-(6-(1-((1-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 5-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (Compound 318) To a solution of 3-(6-(1-((1-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5- ((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (1.0 eq.) in anhydrous THF is added 1M TBAF in THF (3.0–10.0 eq.) at 0 °C under nitrogen atmosphere and the reaction mixture is stirred at ambient temperature for two hours. After completion of the reaction as indicated by UPLC, the reaction mixture is subjected to standard work-up procedure to afford 3-(6-(1-((1-(5-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-5-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (Compound 318). Synthesis 142: Synthesis of 3-[5-[4-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]cyclohexyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 107): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (70 mg, 89.94 μmol, hydrochloric acid) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]cyclohexyl]acetic acid (1) (28.74 mg, 71.96 μmol, no salt) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (296.80 mg, 2.30 mmol, 0.4 mL) followed by addition of HATU (51.30 mg, 134.92 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. Then the reaction mixture was diluted with ice-cold water (1 mL) to get solid. The obtained solid was filtered to get crude product. The crude compound was purified by Prep-HPLC to afford 3-[5-[4-[2-[4-[5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]-2-oxo-ethyl]cyclohexyl]-3-methyl-2-oxo-benzimidazol-1- yl]piperidine-2,6-dione (Compound 107) (35 mg, 30.82 μmol, 34.26% yield, 98.9% purity, no salt) as off white solid. Prep-HPLC condition: Column/dimensions :X-BRIDGE C18 (19*250*5μm); M N WATER(AQ); Mobile phase B : 100% Acetonitrile; Gradient (Time/%B) :0/10,2/15,10/55,14/55 ; Flow rate : 18 mL/min ; Solubility : Acetonitrile+WATER+THF; LCMS (ES+): m/z 1123.53 [M+H]⁺; Retention time (min): 0.3+ 0.05; ¹H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 10.14–9.92 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.38–7.31 (m, 2H), 7.08 (d, J = 10.8 Hz, 1H), 7.02–6.87 (m, 3H), 6.65 (s, 1H), 5.37–5.14 (m, 4H), 4.52 (d, J = 4.8 Hz, 2H), 4.41– 4.23 (m, 2H), 4.17–3.88 (m, 4H), 3.67–3.48 (m, 6H), 3.42–3.33 (m, 3H), 3.13–2.98 (m, 3H), 2.92–2.77 (m, 2H), 2.74–2.54 (m, 3H), 2.44–2.18 (m, 6H), 2.14–1.98 (m, 5H), 1.89–1.68 (m, 7H), 1.63–1.44 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 143: Synthesis of 3-[4-[4-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 108) To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (A-6) (70 mg, 89.94 μmol, hydrochloric acid) and 2-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-4-yl]-4-piperidyl]acetic acid (1) (31.44 mg, 71.96 μmol, hydrochloric acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (34.87 mg, 269.83 μmol, 47.00 μL) followed by addition HATU (51.30 mg, 134.92 μmol). The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtain crude. The crude was purified by Prep-HPLC to afford the product 3-[4-[4-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-1-piperidyl]- 3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Compound 108) (20 mg, 16.90 μmol, 18.79% yield, 95.01% purity, no salt) as a pale pink solid. Column/dimensions: X-BRIDGE C18 (19*250); Mobile phase A: 10mm AMMONIUM ACETATE IN WATER; Mobile phase B: 100% Acetonitrile; Gradient (Time/%B):0/10, 2/30, 13/95; Flow rate: 18mL/min; Solubility: WATER+ACN+THF. LCMS data: m/z 1124.99 [M+H]⁺. Retention time (min): 3.10.¹H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 10.08–9.92 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.36–7.31 (m, 2H), 7.03–6.95 (m, 2H), 6.93–6.84 (m, 2H), 6.65 (s, 1H), 5.37–5.15 (m, 4H), 4.53 (d, J = 5.6 Hz, 2H), 4.41–4.24 (m, 2H), 4.16–3.92 (m, 4H), 3.64–3.49 (m, 10H), 3.12–2.99 (m, 5H), 2.93–2.78 (m, 2H), 2.72–2.57 (m, 2H), 2.42–2.30 (m, 5H), 2.14–1.95 (m, 5H), 1.86–1.72 (m, 9H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 144: Synthesis of 3-[6-[4-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-

1-yl]-2-oxo-ethyl]cyclohexyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 109): To a stirred solution of 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6- yl]cyclohexyl]acetic acid 2 (35.79 mg, 93.35 μmol) in N,N-dimethylformamide (1.2 mL) was added DIPEA (0.04 mL , 269.83 μmol), HATU (51.30 mg, 134.92 μmol) and [5-[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2- yl]-piperazin-1-yl-methanone 1 (70 mg, 89.94 μmol, hydrochloric acid salt). The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was lyophilized to obtained crude which was purified by prep-HPLC method to afford 3-[6-[4-[2-[4- [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]cyclohexyl]- 1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 109 (22 mg, 22 % yield) as an off white solid. LCMS (ESI): m/z 1107.96 [M+H]⁺. Prep-HPLC method: [Column/dimensions: X- BRIDGE C18 (19*150), Mobile phase A: 10 mm AA Water, Mobile phase B: 100% Acetonitrile, Gradient (Time/%B):0/10, 2/20, 15/95, Flow rate: 18 mL/min, Solubility: Water + Acetonitrile + THF]. ¹H-NMR (400 MHz, DMSO-d6) δ: 10.9 (s, 1H), 9.98 (bs, 1H), 9.19 (s, 1H), 7.76 (q, J = 9.2, 6.0 Hz, 1H), 7.60–7.57 (m, 1H), 7.42–7.40 (d, J = 10 Hz, 1H), 7.37–7.32 (m, 2H), 7.09–7.01 (m, 2H), 6.66 (s, 1H), 5.42–5.15 (m, 3H), 4.52 (s, 2H), 4.34–4.29 (m, 3H), 4.13–4.1 (m, 1H), 4.09–4.0 (m, 3H), 3.97–3.95 (d, J = 5.6 Hz, 2H), 3.65–3.5 (m, 6H), 3.12–2.95 (m, 3H), 2.81 (m, 1H), 2.65–2.6 (m, 2H), 2.39–2.25 (m, 4H), 2.22–1.95 (m, 5H), 1.86–1.72 (m, 9H), 1.70–1.51 (m, 5H), 1.25–1.05 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 145: Synthesis of 3-[3-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]phenoxy]piperidine-2,6-dione (Compound 110): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (70 mg, 89.94 μmol, hydrochloric acid) (A-6) and 2-[4-[3-[(2,6-dioxo-3-piperidyl)oxy]phenyl]-1- piperidyl]acetic acid (33.13 mg, 71.96 μmol, trifluoroacetic acid) (1) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (34.87 mg, 269.83 μmol, 47.00 μL) followed by HATU (51.30 mg, 134.92 μmol) portion wise. The reaction mixture was stirred at 25 °C for 12 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) to get precipitated solid. The solid was filtered to get crude product. The crude was purified by prep-HPLC to afford product 3-[3-[1-[2-[4-[5-[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]phenoxy]piperidine-2,6-dione (Compound 110) (0.01488 g, 13.51 μmol, 15.02% yield, 97.19% purity, no salt) as an off-white solid. Prep- HPLC condition: Column/dimensions: X-BRIDGE C18 (19*250)5μ; Mobile phase A :10mM Ammonium acetate in Water. Mobile phase B : Acetonitrile; Gradient (Time/%B) :0/10,2/20,13/90; Flow rate: 18 mL/min; Solubility : Acetonitrile+ THF; Spot visualization: UV active compound; LCMS (ES+): m/z 1170.65 [M+H]⁺; Retention time (min): 5.70; ¹H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 10.14–9.92 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (m, 1H), 7.36–7.32 (m, 2H), 7.20-7.16 (t, J=7.6Hz, 1H), 7.01-7.00 (m,1H), 6.87-6.81 (m, 3H), 6.62 (s,1H), 5.21-5.19 (m, 4H), 4.53-4.51(m, 2H) ,4.12-4.05(m, 4H), 3.63 (bs, 4H), 3.49 (s, 2H), 3.18(s, 2H), 3.10–3.06 (m, 3H), 3.00(m, 2H), 2.93-2.90 (m, 1H), 2.61 (m, 1H), 2.56(m, 2H), 2.49-2.44 (m, 3H),2.35-2.04(m,8H)1.85-1.75(m,7H)1.73-1.71(bs,2H) 0.71 (t, J = 7.2 Hz, 3H). Synthesis 146: Synthesis of 3-[5-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-

1-yl]-2-oxo-ethyl]-4-piperidyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione (Compound 111) To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (70 mg, 89.94 μmol, hydrochloric acid) (A-6) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo- benzo[cd]indol-5-yl]-1-piperidyl]acetic acid (38.53 mg, 71.96 μmol, trifluoroacetic acid) (1) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (34.87 mg, 269.83 μmol, 47.00 μL) followed by HATU (51.30 mg, 134.92 μmol) portion wise. The reaction mixture was stirred at 25 °C for 12 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (5 mL) to get precipitated solid. A solid was filtered to get crude product. The crude was purified by prep-HPLC to afford product of 3-[5-[1- [2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]- 2-oxo-benzo[cd]indol-1-yl]piperidine-26-dione (Compound 111) (15.8 mg, 13.67 μmol, 17.73% yield, 97.24% purity, no salt) as an off-white solid. Prep-HPLC condition: Column:X- BRIDGE C18, 5 μm (250mmX19mm); Mobile Phase A:10MM AMMONIUM ACETATE IN WATER B: CAN; Gradient (T%B): 0/10,2/15,13/85 ; Flow Rate: 18mL/min; Sample Diluent: ACN+Water+THF; LCMS (ES+): m/z 1143.83 [M-H]-; Retention time (min): 5.53; ¹H NMR (400 MHz, DMSO-d6): δ 11.15 (s, 1H), 10.14–9.92 (bs, 1H), 9.19 (s, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.83 (d, J=8.4Hz, 1H), 7.77-7.73 (m, , 2H), 7.55 (t, J=7.6Hz,1H), 7.36-7.32 (m, 2H), 7.14 (d, J=7.2Hz,1H), 7.01 (m, 1H), 6.66 (s, 1H), 5.43–5.20 (m, 4H), 4.53-4.52 (m, 2H), 4.35-4.30 (m, 2H), 4.15-4.06 (m, 4H), 3.67–3.51 (m, 8H), 3.10-2.94(m, 5H), 2.82-2.76 (m, 3H), 2.67–2.62 (m, 1H), 2.33–2.32(m, 4H), 2.12-1.99 (m, 5H),1.85-1.75(m,9H) 0.71 (t, J = 7.2 Hz, 3H). Synthesis 147: Synthesis of 3-[3-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]-2-oxo-ethyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 112): To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahyd l-methanone (A-6) (70 mg, 89.94 μmol, hydrochloric acid) and 2-[4-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]acetic acid (1) (33.06 mg, 71.96 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (11.62 mg, 89.94 μmol, 15.67 μL)followed by addition HATU (51.30 mg, 134.92 μmol)The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtain crude. The crude was purified by Prep-HPLC to afford the product 3-[3- [1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4- piperidyl]anilino]piperidine-2,6-dione (Compound 112) (15 mg, 13.17 μmol, 14.64% yield, 93.88% purity, no salt) as an off-white solid. Prep-HPLC condition: Column/dimensions: X- BRIDGE C18 (19*250*5μm); Mobile phase A: 10 MM AMMONIUM ACETATE IN WATER (AQ); Mobile phase B: 100% Acetonitrile; Gradient (Time/%B):0/10, 2/10, 15/75; Flow rate: 18 mL/min; Solubility: Acetonitrile+WATER+THF; LCMS data: m/z 1069.56 [M+H]⁺; Retention time (min): 2.57; ¹H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 10.12–9.90 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.38–7.31 (m, 2H), 7.02–6.96 (m, 2H), 6.65 (bs, 1H), 6.55 (bs, 1H), 6.51–6.43 (m, 2H), 5.73 (d, J = 7.2 Hz, 1H), 5.36–5.15 (m, 3H), 4.52 (d, J = 5.6 Hz, 2H), 4.41–4.24 (m, 3H), 4.14–3.89 (m, 4H), 3.67–3.46 (m, 6H), 3.17 (bs, 2H), 3.11–2.99 (m, 4H), 2.94–2.70 (m, 4H), 2.59 (bs, 2H), 2.42–2.29 (m, 2H), 2.14–1.97 (m, 7H), 1.91–1.75 (m, 8H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 148: Synthesis of N-[5-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1-piperidyl]pentyl]-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-

d]pyrimidin-4-yl]-N-methyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxamide (Compound 143): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (80 mg, 118.75 μmol, no salt) and 3-[3-methyl-5-[1-[5-(methylamino)pentyl]-4-piperidyl]-2-oxo-benzimidazol- 1-yl]piperidine-2,6-dione (1) (41.95 mg, 81.54 μmol, hydrochloric acid*2) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (46.04 mg, 356.25 μmol, 62.05 μL) followed by addition of HATU (67.73 mg, 178.13 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with ice-cold water (2ml) to get solid. The obtained solid was filtered to get crude product. The crude compound was purified by Prep-HPLC to afford N-[5-[4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]pentyl]-5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-N-methyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (Compound 143) (8 mg 708 μmol, 5.96%yield, 97.07% purity, no salt). Column/dimensions : X-BRIDGE C18(19*250); Mobile phase A : 10mM Ammonium acetate in water; Mobile phase B : 100% acetonitrile; Gradient (Time/%B) :0/20,2/20,14/85; Flow rate : 18mL/min Solubility : THF+ACN; LCMS (ES+): m/z 1097.70 [M+H]⁺; Retention time (min): 5.74; ¹H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 10.08–9.88 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.4 Hz, 1H), 7.37–7.31 (m, 2H), 7.10– 6.96 (m, 3H), 6.92–6.86 (m, 1H), 6.59 (d, J = 5.6 Hz, 1H), 5.34–5.13 (m, 4H), 4.51 (bs, 2H), 4.41–4.23 (m, 2H), 4.17–4.04 (m, 2H), 3.72–3.64 (m, 1H), 3.44–3.35 (m, 4H), 3.11–2.77 (m, 10H), 2.64–2.57 (m, 1H), 2.43–2.25 (m, 4H), 2.16–1.89 (m, 8H), 1.87–1.43 (m, 13H), 1.36–1.25 (m, 2H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 149: Synthesis of 3-[4-[1-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 144):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 2 (54.53 mg, 76.79 μmol, HCl salt) and 3-[4-[1-(4-piperidyl)-4-piperidyl] anilino]piperidine-2,6-dione 1 (25 mg, 61.43 μmol, HCl salt) in N,N-dimethylformamide (2 mL) were added DIPEA (361.14 μL, 200.07 μmol) and HATU (29.20 mg, 76.79 μmol) at room temperature and was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure and the crude obtained was purified by Prep HPLC method to afford 3-[4-[1-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]-4- piperidyl]anilino]piperidine-2,6-dione Compound 144 (10 mg, 12% yield) as an off white solid. LC-MS (ES⁺): m/z 1026.84 [M+H]⁺. Prep-HPLC method: [Column/dimensions: XSELECT C18 (10*250, 5μm), Mobile phase A: 0.1% FA in water, Mobile phase B: 100% ACN Gradient, (Time/%B): 0.1/10, 1/10, 5/23, 10.50/23, 10.60/98, 13/98, flow rate: 17 mL/min, Solubility: THF+WATER]. ¹H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 9.90 (s, 1H), 9.20 (s, 1H), 7.80-7.70 (m, 1H), 7.40-7.30 (m, 2H), 7.01 (d, J = 2.00 Hz, 1H), 6.93 (d, J = 8.40 Hz, 2H), 6.59 (d, J = 8.40 Hz, 3H), 5.63 (d, J = 7.60 Hz, 1H), 5.40-5.10 (m, 3H), 4.70-4.60 (m, 1H), 4.60-4.45 (m, 3H), 4.40-4.20 (m, 3H), 4.20-4.10 (m, 1H), 4.10 (d, J = 16.40 Hz, 1H),3.10-3.00 (m, 4H), 3.00-2.70 (m, 6H), 2.60-2.50 (m, 4H), 2.30-2.20 (m, 4H), 2.15-1.95 (m, 6H), 1.91 (s, 2H), 1.90- 1.70 (m, 6H), 1.70-1.60 (m, 2H), 1.60-1.50 (m, 2H), 1.45-1.30 (m, 2H), 1.24 (s, 2H). Synthesis 150: Synthesis of 3-[4-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3- azaspiro[5.5]undecan-9-yl]anilino]piperidine-2,6-dione (Compound 145):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (80 mg, 112.65 μmol, hydrochloric acid)and 3-[4-(3-azaspiro[5.5]undecan-9-yl)anilino]piperidine-2,6-dione (1) (35.32 mg, 90.12 μmol, hydrochloric acid) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (43.68 mg, 337.96 μmol, 58.87 μL) followed by addition of HATU (64.25 mg, 168.98 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtain the crude. The crude was purified by Prep-HPLC to afford the product 3-[4-[3-[5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-3-azaspiro[5.5]undecan-9-yl]anilino]piperidine-2,6-dione (Compound 145) (13 mg, 11.59 μmol, 10.29% yield, 90.16% purity, no salt) as an off-white solid. Column: X-BRIDGE C18, 5 μm (250mmX19mm); Mobile Phase A: 10 mM Ammonium acetate in water; Mobile Phase B: CAN; Gradient (T%B): 0/20, 2/30, 12/80; Flow Rate: 18mL/min; Sample Diluent: ACN+water+THF; LCMS data: m/z 1011.59 [M+H]⁺; Retention time (min): 3.26; ¹H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 9.92 (s, 1H), 9.20 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.38–7.31 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.98–6.92 (m, 2H), 6.62–6.55 (m, 3H), 5.61 (d, J = 7.2 Hz, 1H), 5.36–5.13 (m, 3H), 4.52 (d, J = 5.6 Hz, 2H), 4.42–4.22 (m, 3H), 4.16–4.05 (m, 2H), 3.83 (bs, 2H), 3.57 (bs, 2H), 3.13–2.99 (m, 3H), 2.85–2.70 (m, 2H), 2.36 (bs, 2H), 2.16–1.98 (m, 6H), 1.91–1.75 (m, 8H), 1.45 (bs, 6H), 1.34–1.13 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 151: Synthesis of 3-((4-(7-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-2,7- diazaspiro[3.5]nonan-2-yl)phenyl)amino)piperidine-2,6-dione (Compound 146) To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (80 mg, 112.65 μmol, hydrochloric acid) and 3-[4-(2,7-diazaspiro[3.5]nonan-2-yl)anilino]piperidine-2,6-dione (32.88 mg, 90.12 μmol) in N,N-dimethylformamide (2 mL) at 0 °C was added DIPEA (43.68 mg, 337.96 μmol, 58.87 μL) followed by addition of HATU (64.25 mg, 168.98 μmol). The reaction mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtain crude. The crude product was purified by Prep-HPLC to afford the product 3-[4-[7-[5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl]anilino]piperidine-2,6-dione (Compound 146) (15 mg, 13.81 μmol, 12.26% yield, 90.61% purity) as an off-white solid. Prep-HPLC condition: Column:X-SELECT C18, 5 μm (100mm ×19mm); Mobile Phase A: 10mM Ammonium acetate in water, Mobile Phase B: CAN; Gradient (T%B):0/5,2/20,13/80; Flow Rate: 18mL/min; Sample Diluent: ACN+Water+THF. LCMS data: m/z 984.78 [M+H]⁺. Retention time (min): 2.64. ¹H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (m, 1H), 7.37–7.32 (m, 2H), 7.00 (s, 1H), 6.60 (m, 3H), 6.28 (d, J = 8.4 Hz, 2H), 5.39–5.13 (m, 4H), 4.52 (bs, 2H), 4.39– 4.21 (m, 3H), 4.19–4.05 (m, 2H), 3.85 (bs, 2H), 3.54 (bs, 2H), 3.47 (s, 4H), 3.13–2.97 (m, 4H), 2.78–2.52 (m, 3H), 2.33 (s, 2H), 2.16–1.96 (m, 5H), 1.92–1.67 (m, 9H), 0.71 (t, J = 7.4 Hz, 3H). Synthesis 152: Synthesis of 3-[4-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin- 1-yl]anilino]piperidine-2,6-dione (Compound 147): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (80 mg, 118.75 μmol, no salt) and 3-(4-piperazin-1-ylanilino)piperidine-2,6-dione (1) (30.86 mg, 95.00 μmol, hydrochloric acid) in N,N-dimethylformamide (1 mL) at 0 °C was added DIPEA (46.04 mg, 356.25 μmol, 62.05 μL) followed by addition of HATU (67.73 mg, 178.13 μmol). Then reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was then diluted with ice-cold water (2ml) to get solid. The obtained solid was filtered to get crude product. The crude compound was purified by Prep-HPLC to afford 3-[4- [4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]anilino]piperidine-2,6- dione (Compound 147) (23 mg, 22.07 μmol, 18.59% yield, 90.6% purity, no salt) as grey solid. Column/dimensions : X-BRIDGE C18(19*250); Mobile phase A : 10mM Ammonium acetate in water; Mobile phase B : 100% acetonitrile; Gradient (Time/%B) :0/10,2/15,11.10/80,11.20/98,13.50/98,13.60/10; Flow rate : 18mL/min; Solubility : WATER+ACN+THF; LCMS (ES+): m/z 944.54 [M+H]⁺; Retention time (min): 2.79; ¹H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 9.92 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.38–7.32 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.65–6.59 (m, 3H), 5.43 (d, J = 7.2 Hz, 1H), 5.37–5.14 (m, 3H), 4.52 (d, J = 5.6 Hz, 2H), 4.41–4.25 (m, 2H), 4.23– 4.14 (m, 5H), 3.72 (bs, 2H), 3.13–2.89 (m, 7H), 2.86–2.68 (m, 2H), 2.62–2.54 (m, 2H), 2.42– 2.33 (m, 2H), 2.16–1.96 (m, 5H), 1.87–1.73 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 153: Synthesis of 3-[6-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3- azaspiro[5.5]undecan-9-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 148):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (60 mg, 84.49 μmol, hydrochloric acid salt) and 3-[6-(3-azaspiro[5.5]undecan-9-yl)-1-methyl-indazol-3- yl]piperidine-2,6-dione 2 (29.13 mg, 67.59 μmol, hydrochloric acid salt) in N,N- dimethylformamide (1 mL) was added DIPEA (32.76 mg, 253.47 μmol), HATU (48.19 mg, 126.73 μmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was lyophilized to get crude which was purified by prep- HPLC to afford 3-[6-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3-azaspiro[5.5]undecan-9-yl]-1-methyl- indazol-3-yl]piperidine-2,6-dione Compound 148 (10 mg, 11% yield) as an off white solid. LCMS (ESI): m/z 1050.98 [M+H]⁺. Prep-HPLC method: Column/dimensions: X-Bridge C18(19*250*5 μ); Mobile phase A : 10 mM Ammonium acetate in water; Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/15, 12/90, Flow rate: 18 mL/min, Solubility: Water+ acetonitrile+ THF.¹H-NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 9.98 (bs, 1H) 9.20 (s, 1H), 7.76 (q, J = 9.2, 6.4 Hz, 1H), 7.58 (d, J = 8, 1H), 7.45 (d, J = 5.6 Hz, 1H), 7.37–7.32 (m, 2H), 6.04–7.00 (m, 3H), 6.58 (s, 1H), 5.36–5.13 (m, 3H), 4.50 (d, J = 5.6 Hz, 2H), 4.42–4.22 (m, 3H), 4.16–4.05 (m, 2H), 3.83 (bs, 2H), 3.57 (bs, 2H), 3.13–2.99 (m, 3H), 2.75–2.60 (m, 3H), 2.4– 2.34 (m, 4H), 2.22–1.98 (m, 5H), 1.91–1.75 (m, 8H), 1.45 (m, 6H), 1.34–1.16 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 154: Synthesis of 1-[6-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3- azaspiro[5.5]undecan-9-yl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (Compound 149): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (A-7) (70 mg, 98.57 μmol, hydrochloric acid) and 1-[6-(3-azaspiro[5.5]undecan-9-yl)-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione (1) (34.06 mg, 78.86 μmol, hydrochloric acid) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (38.22 mg, 295.71 μmol, 51.51 μL) followed by addition of HATU (56.22 mg, 147.86 μmol). The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was lyophilized to obtain crude. The crude was purified by Prep-HPLC to afford the product 1-[6-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3-azaspiro[5.5]undecan-9-yl]-1-methyl- indazol-3-yl]hexahydropyrimidine-2,4-dione (Compound 149) (18 mg, 16.60 μmol, 16.84% yield, 96.94% purity, no salt) as an off-white solid. Prep-HPLC Conditions: Column/dimensions: X-BRIDGE C18 (19*250)5μ; Mobile phase A: 10mM ammonium acetate in water; Mobile phase B: acetonitrile; Gradient (Time/%B):0/2, /2,12/65,12.1/98,14/98,14.1/2,16/2; Flow rate: 18 mL/min; Solubility: Acetonitrile+ THF; LCMS (ES+): m/z 1051.94 [M+H]⁺ _; Retention time (min): 3.19; ¹H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 10.12–9.92 (bs, 1H), 9.20 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 5.6 Hz, 1H), 7.37–7.31 (m, 2H), 7.06–7.00 (m, 2H), 6.58 (bs, 1H), 5.37–5.14 (m, 3H), 4.51 (d, J = 5.2 Hz, 2H), 4.40– 4.05 (m, 4H), 3.97–3.82 (m, 7H), 3.61 (bs, 2H), 3.13–2.99 (m, 3H), 2.32 (bs, 3H), 2.16–1.97 (m, 4H), 1.88–1.63 (m, 15H), 1.37–1.21 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 155: Synthesis of 3-(6-(9-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-3,9- diazaspiro[5.5]undecan-3-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound 150)

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (65 mg, 91.53 μmol) in N,N-dimethylformamide (0.5 mL) at 0 °C was added DIPEA (35.49 mg, 274.59 μmol, 47.83 μL) followed by HATU (52.20 mg, 137.30 μmol). After 5 minutes, 3-[6-(3,9- diazaspiro[5.5]undecan-3-yl)-1-methyl-indazol-3-yl]piperidine-2,6-dione (31.63 mg, 73.22 μmol, hydrochloric acid) was added. Then the reaction mixture was stirred at 25 C for 16 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice- cold water (5 mL) and diluted with acetonitrile (0.5 mL). Reaction mixture was lyophilized to obtained crude, which was purified by prep-HPLC to afford 3-[6-[3-[5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-3,9-diazaspiro[5.5]undecan-9-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 150 (10 mg, 9.33 μmol, 10.19% yield, 98.04% purity, no salt) as an off white solid. LC-MS (ESI): m/z 1049.77 [M-H]-. Prep-HPLC Method: Column/dimensions: X-Bridge c18(19*250*5 μ); Mobile phase A: 10mm Ammonium acetate in water; Mobile phase B: 100% acetonitrile Gradient (Time/%B) :0/20,2/20,10/55,12/55; Flow rate: 18mL/min; Solubility : ACN+WATER+THF; Retention time: 4.31. ¹H NMR (400 MHz, DMSO-d6):δ 10.92(s, 1H),9.98 (bs, 1H) 9.20 (s, 1H), 7.77-7.74 (m, 1H),7.47 (d, J = 9.2 Hz, 1H), 7.36-7.32 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 9.2 Hz,1H), 6.83 (s, 1H), 6.58 (s, 1H), 5.40-5.15 (m, 3H), 4.51-4.49 (m,2H), 4.40 – 4.31 (m, 1H), 4.29 – 4.22 (m, 2H), 4.12-4.08 (m, 1H), 4.08- 4.06(m, 1H), 3.89(s, 5H), 3.61(bs, 2H), 3.24-3.22(m, 4H), 3.12-2.98(m, 3H), 2.82(m, 1H), 2.63- 2.59(m, 2H),2.32-2.30 (m, 2H),2.21-1.93(m, 5H), 1.90-1.62(m, 5H), 1.53(m, 4H), 1.49(m, 4H),0.71(t,3H) ppm. Synthesis 156: Synthesis of 1-[6-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3,9- diazaspiro[5.5]undecan-9-yl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (Compound 151): To a solution 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 1 (77.90 mg, 109.69 μmol, HCl salt) and 1-[6-(3,9-diazaspiro[5.5]undecan-3-yl)-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4- dione 2 (80 mg, 156.71 μmol, trifluoromethanesulfonic acid salt) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (0.6 mL, 3.44 mmol) and HATU (89.38 mg, 235.06 μmol). The resulting mixture was stirred at room temperature for 16 hours. The crude mixture was lyophilized to obtain crude which was purified by prep HPLC to afford 1-[6-[3-[5-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3,9-diazaspiro[5.5]undecan-9-yl]-1- methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione Compound 151 (50 mg, 29 % yield, TFA salt) as an off-white solid. LC-MS (ESI): m/z 1052.83 [M+H]⁺. Preparative HPLC method: Column/dimension X SELECT C18 5 (100 X19 ) M bile phase A : 0.1% TFA in water; Mobile phase B : 100% acetonitrile; Gradient (Time/%B) : 0/10,2/15,8.35/49,8.50/98,11/98,11.10/10,13.50/10; Flow rate : 18 mL/min; Solubility : Water+Acetonitrile+THF].¹H NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1H), 10.50 (s, 1H), 10.01 (s, 1H), 9.28 (s, 1H), 7.79-7.75 (m, 1H), 7.46-7.43 (d, J = 12 Hz, 3H), 7.38-7.33 (m, 2H), 7.20- 6.85 (m, 2H), 6.68 (s, 1H), 5.65-5.52 (m, 1H), 5.35-5.19 (m, 2H), 4.62-4.36 (m, 6H), 3.90-3.83 (m, 11H), 3.37-3.27 (m, 4H), 2.75-2.71 (t, J= 8 Hz, 2H), 2.63-2.59 (m, 2H), 2.49-2.19 (m, 4H), 2.08-1.90 (m, 4H), 1.75-1.65 (m, 4H), 1.60-1.50 (m, 4H), 0.72-0.68 (t, J = 8 Hz, 3H). Synthesis 157: Synthesis of 3-[7-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3- azaspiro[5.5]undecan-9-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 152): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (65 mg, 91.53 μmol, hydrochloric acid salt) and 3 [7 (3 azaspiro[55]undecan 9-yl)-1-methyl-indazol-3- yl]piperidine-2,6-dione 2 (31.56 mg, 73.22 μmol, hydrochloric acid salt) in N,N- dimethylformamide (1.5 mL) was added DIPEA (35.49 mg, 274.59 μmol, 47.83 μL), HATU (52.20 mg, 137.30 μmol) and the reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was lyophilized to obtained crude which was purified by SFC- Prep method to afford 3-[7-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3-azaspiro[5.5]undecan-9-yl]- 1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 152 (14 mg, 13% yield) as an off white solid. LC-MS (ES⁺): m/z 1050.75 [M+H]⁺. SFC-Prep Method: [Column/dimensions: YMC PAK DIOL-120 (30x250) mm, 5μ, %CO₂: 55%, %Co solvent: 45% (0.1 % methanolic ammonia in ACN- methanol) Flow: 100 mL/min, Back Pressure: 100 bar, Temperature: 30 ^̊C, UV: 220 nm, Solubility: methanol+Acetonitrile+THF, No. of injections: 6, Total purification time: 01:30 hour, Run time per injection: 07:00 mins]; ¹H NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 9.20 (s, 1H), 8.80 (s, 1H), 7.78–7.74 (m, 1H), 7.52 (d, J = 8 Hz, 1H), 7.37–7.25 (m, 3H), 7.06–7.00 (m, 2H), 6.58 (s, 1H), 5.42–5.09 (m, 3H), 4.51 (d, J = 5.2 Hz, 2H), 4.43–4.25 (m, 3H), 4.20 (s, 3H), 4.15 (m, 1H), 4.09 (m, 1H), 3.87 (bs, 2H), 3.60 (bs, 2H), 3.12–3.00 (m, 3H), 2.82 (m, 1H), 2.62–2.60 (m, 2H), 2.35–2.31 (m, 3H), 2.22–1.98 (m, 6H), 1.92–1.82 (m, 5H), 1.80–1.56 (m, 5H), 1.50–1.31 (m, 6H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 158: Synthesis of 1-[7-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3- azaspiro[5.5]undecan-9-yl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (Compound 153):

To a stirred solution of 1-[7-(3-azaspiro[5.5]undecan-9-yl)-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione A-7 (34.06 mg, 78.86 μmol, hydrochloric acid salt) in N,N- dimethylformamide (1.5 mL) was added DIPEA (0.05 mL, 295.71 μmol) HATU (56.22 mg, 147.86 μmol) and 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 1 (70 mg, 98.57 μmol, hydrochloric acid salt) at 0 °C. The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was lyophilized to obtain crude material which was purified by prep-HPLC method to afford 1-[7-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3-azaspiro[5.5]undecan-9-yl]-1-methyl- indazol-3-yl]hexahydropyrimidine-2,4-dione Compound 153 (20 mg, 19 % yield) as an off- white solid. LCMS (ESI): m/z 1051.84 [M+H]⁺. Prep-HPLC method: [Column/dimensions: X- BRIDGE-C18; 250x20mm; 5u, Mobile phase A: 10 mM ammonium acetate in water, Mobile phase B: acetonitrile, Gradient (Time/%B): 0/20, 2/35, 15/95, Flow rate: 18mL/min, Solubility: Water+Acetonitrile+THF]. ¹H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 10.12–9.92 (bs, 1H), 9.15 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.44 (d, J = 8 Hz, 1H), 7.37–7.27 (m, 3H), 7.07–7.05 (m, 1H), 7.01 (d, J = 2 Hz, 1H),6.58 (s, 1H), 5.35–5.20 (m, 3H), 4.51 (d, J = 5.6 Hz, 2H), 4.42–4.22 (m, 2H), 4.19–4.05 (m, 5H), 3.86 (t, J = 6.4 Hz, 4H).3.6 (bs, 2H), 3.04–2.82 (m, 4H), 2.80–2.77 (m, 1H), 2.75 (t, J = 1.6 Hz 2H), 2.14–2.11(m, 2H), 2.08–2.00 (m, 4H),1.91– 1.81 (m, 6H), 1.52–1.49 (m, 6H), 1.38 (bs, 4H), 0.71 (t, J = 7.2 Hz, 3H) ppm. Synthesis 159: Synthesis of 3-[7-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl] 4678 tetrahydropyrazolo[15 a][14]diazepine 2-carbonyl]-3,9- diazaspiro[5.5]-undecan-9-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 154): To a solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (60 mg, 84.49 μmol, HCl salt) and 3-[7-(3,9-diazaspiro[5.5]undecan-3-yl)-1-methyl-indazol-3-yl]piperidine-2,6-dione 1 (29.20 mg, 67.59 μmol, HCl salt) in N,N-dimethylformamide (1 mL) were added HATU (48.19 mg, 126.73 μmol) N,N-diisopropylethylamine (296.80 mg, 2.30 mmol, 0.4 mL) and the resulting mixture was stirred at room temperature for 16 hours. The crude mixture was the lyophilized to obtained the crude product which was purified by preparative HPLC to afford 3-[7-[3-[5-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3,9-diazaspiro[5.5]undecan-9-yl]-1- methyl-indazol-3-yl]piperidine-2,6-dione Compound 154 (18 mg, 20 % yield) as an off-white solid. LCMS (ESI): m/z 1051.80 [M+H]⁺. Prep-HPLC method: Column/dimensions: X- BRIDGE C18 (19*100)5 M bil h A 10 M i e in water; Mobile phase B: Acetonitrile Gradient (Time/%B): 0/20,2/20,15/80; Flow rate : 18 mL/min; Solubility : Acetonitrile+ THF]; ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H), 10.03 (s, 1H), 9.20 (s, 1H), 7.78-7.74 (m, 1H), 7.38-7.32 (m, 3H), 7.05-6.90 (m, 2H), 6.59 (s, 1H), 5.40-5.20 (m, 3H), 4.52-4.50 (m, 2H), 4.34-4.31 (m, 6H), 4.13-4.06 (m, 2H), 3.89 (bs, 2H), 3.62 (bs, 2H), 3.53 (bs, 5H), 3.10-2.83 (m, 8H), 2.63-2.50 (m, 2H), 2.34 (m, 4H), 2.14-1.99 (m, 5H), 1.87-1.75 (m, 6H), 1.65 (bs, 4H), 1.40 (m, 2H), 0.73 (t, J = 14.4 Hz, 2H) ppm. Synthesis 160: Synthesis of 1-[7-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3,9- diazaspiro[5.5]undecan-9-yl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (Compound 155): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[15 a][14]diazepine 2 carboxylic acid A-7 (70 mg, 98.57 μmol, hydrochloric acid salt) and 1-[7-(3,9-diazaspiro[5.5]undecan-3-yl)-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione 2 (31.27 mg, 61.24 μmol, trifluoroacetic acid salt ) in N,N- dimethylformamide (1 mL) was added DIPEA (0.05 mL,98.57 μmol) and HATU (56.22 mg, 147.86 μmol). The reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was lyophilized to get crude compound which was purified by prep-HPLC to afford 1-[7-[3-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-3,9-diazaspiro[5.5]undecan-9-yl]-1- methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione Compound 155 (10 mg, 8% yield) as an off-white solid. LCMS (ESI): m/z 1052.81 [M+H]⁺. Prep-HPLC method: Column/dimensions: X-BRIDGE C18 (19 * 250) Mobile phase A: 10 mM Ammonium acetate in water Mobile phase B: 100% acetonitrile to afford Gradient (Time/%B): 0/10, 2/20,13.40/85 Flow rate: 18 mL/min Solubility: WATER+MeCN+THF.¹H NMR (400 MHz, DMSO-d6): δ 10.55 (s, 1H), 10.02 (bs, 1H), 9.20 (s, 1H), 7.78–7.74 (m, 1H), 7.37–7.27 (m, 3H), 7.06–6.98 (m, 3H), 6.59 (s, 1H), 5.41– 5.10 (m, 3H), 4.51 (d, J = 5.6 Hz, 2H), 4.41–4.20 (m, 5H), 4.19–4.05 (m, 2H), 3.91–3.82 (m, 4H), 3.63 (bs, 2H), 3.10–2.92 (m, 6H), 2.82 (m, 2H), 2.72 (t, J = 6.8 Hz, 2H), 2.60 (m, 1H), 2.40–2.32 (m, 2H), 2.19–1.95 (m, 5H), 1.89–1.72 (m, 6H), 1.75 (m, 4H), 1.65 (m, 2H), 0.71 (t, J = 7.2 Hz, 1H).ppm. Synthesis 161: Synthesis of 3-[7-[2-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-2- azaspiro[3.5]nonan-7-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 156)

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (70 mg, 98.57 μmol, hydrochloric acid salt) and 3-[7-(2-azaspiro[3.5]nonan-7-yl)-1-methyl-indazol-3-yl]piperidine- 2,6-dione 2 (31.77 mg, 78.86 μmol, hydrochloric acid salt) in N,N-dimethylformamide (1 mL) was added DIPEA (38.22 mg, 295.71 μmol) and HATU (56.22 mg, 147.86 μmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was lyophilized to get crude product which was purified by Prep-HPLC to afford.3-[7- [2-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-2-azaspiro[3.5]nonan-7-yl]-1-methyl- indazol-3-yl]piperidine-2,6-dione Compound 156 (15 mg, 14% yield) as an off white solid. LCMS (ESI): m/z 1037.72 [M+H]⁺. Prep-HPLC method: [Column: X-SELECT C18, 5 Âμm (100mmX19mm), Mobile Phase A: 10 mM Ammonium acetate in water, B: ACN, Gradient (T%B):0/15,2/25,15/95 Flow Rate: 18mL/min Sample Diluent: ACN+Water+THF].¹H NMR (400 MHz, DMSO-d6): δ 10.9 (s, 1H), 9.91(s, 1H), 9.20 (s, 1H), 7.78–7.74 (m, 1H), 7.52 (d, J = 8 Hz 1H), 7.37–7.32 (m, 2H), 7.24 (t, J = 8 Hz, 1H), 7.08-7.02 (m, 1H), 7.00 (d, J = 2 Hz 1H), 6.67 (d, J = 1.2 Hz 1H), 5.45–5.15 (m, 3H), 4.5–4.51 (m, 2H), 4.40–4.25 (m, 4H), 4.20 (s, 3H), 4.00–4.2 (m, 3H), 3.8 (s, 1H), 3.18 (s, 1H), 3.28 (m, 1H), 3.10–2.98 (m, 3H), 2.83 (m, 1H), 2.61 (m, 2H), 2.40–2.31 (m, 3H), 2.20–1.98 (m, 7H), 1.90–1.80 (m, 2H), 1.79–1.70 (m, 6H), 1.59 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 162: Synthesis of 3-[7-[2-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-2,7- diazaspiro[3.5]nonan-7-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 157) To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (70 mg, 98.57 μmol, hydrochloric acid salt) and 3-[7-(2,7-diazaspiro[3.5]nonan-7-yl)-1-methyl-indazol-3- yl]piperidine-2,6-dione 2 (31.85 mg, 78.86 μmol, hydrochloric acid salt) in N,N- dimethylformamide (1 mL) was added DIPEA (51.51 μL ,295.71 μmol,) and HATU (56.22 mg, 147.86 μmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was lyophilized to get crude compound which was purified by prep-HPLC to afford 3-[7-[2-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-2,7-diazaspiro[3.5]nonan-7- yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 157 (12 mg, 10% yield, trifluoroacetic acid salt) as an off-white solid. LC-MS (ES+): m/z 1023.78 [M+H]⁺. Prep-HPLC method: [Column: X-bridge C18, 5 μm (150mmX19mm), MOBILE Phase A: 0.1% TFA in water, B: ACN Gradient (T%B):0/15, 2/20, 10/67, Flow Rate: 18mL/min, Sample Diluent: ACN+Water+THF]. ¹H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1H),10.62 (bs, 1H), 9.93 (s, 1H), 9.27 (s, 1H), 7.79–7.75 (m, 1H), 7.39–7.33 (m, 3H), 7.002–7.00 (m, 2H), 6.78 (s, 1H), 5.65–5.49 (m, 1H), 5.38–5.19 (m, 2H), 4.61–4.50 (m, 4H), 4.45–4.20 (m, 8H), 3.91–3.71 (m, 6H), 3.19 (s, 3H), 4.60 (m, 4H), 2.42–2.35 (m, 5H), 2.20–2.11 (m, 6H), 2.10–1.91(m, 4H), 0.70 (t ,J = 7.2 Hz, 3H) ppm. Synthesis 163: Synthesis of 3-[7-[2-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-2- azaspiro[4.5]decan-8-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 158): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (70 mg, 98.57 μmol, hydrochloric acid salt) and 3-[7-(2-azaspiro[4.5]decan-8-yl)-1-methyl-indazol-3-yl]piperidine- 2,6-dione (30.00 mg, 71.96 μmol, hydrochloric acid salt) 2 in N,N-dimethylformamide (1 mL) was added DIPEA ( l ) d ( 47.86 μmol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was lyophilized to get crude compound which was purified by prep- to afford 3-[7-[2-[5-[7-(8-ethyl- 7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-2-azaspiro[4.5]decan-8-yl]-1-methyl- indazol-3-yl]piperidine-2,6-dione Compound 158 (12 mg, 12% yield) as an off-white solid LCMS (ESI): m/z 1036.80[M+H]⁺. Prep-HPLC method: Column/dimensions: X-BRIDGE-C18; 150 x 19 mm; 5μ Mobile phase A: 10 mM ammonium acetate in water, Mobile phase B: acetonitrile Gradient (Time/%B): 0/10, 2/20, 11/75, 11.10/98, 13.50/98, 13.60/10,15/10, Flow rate: 18 mL/min Solubility: WATER+Acetonitrile+THF. ¹H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 9.95 (s, 1H), 9.28 (s, 1H), 7.79-7.76 (m, 1H), 7.54-7.52 (m,1H),7.38-7.29 (m, 3H),7.20-6.94 (m,3H),6.78 (bs,1H), 5.52-5.50 (m, 1H), 5.40-5.19 (m, 2H), 4.71-4.30 (m, 7 H) 4.36-4.19 (m,3H), 3.92- 3.70 (m, 3.35 (m, 5H),3.51 (m, 2H), 3.38-3H), 2.65-2.61 (m, 2H), 2.49- 2.40 (m,4H), 2.37-2.10 (m, 6H), 1.93-1.87(m,3H), 1.80-1.65 (m, 6H), 1.23 (s,1H) 0.71 (t, J = 7.2 Hz, 3H). Synthesis 164: Synthesis of 3-[7-[2-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-2,8- diazaspiro[4.5]decan-8-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 159)

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (70 mg, 98.57 μmol, hydrochloric acid salt) and 3-[7-(2,8-diazaspiro[4.5]decan-8-yl)-1-methyl-indazol-3- yl]piperidine-2,6-dione 2 (32.96 mg, 78.86 μmol, hydrochloric acid salt) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (38.22 mg, 295.71 μmol) followed by addition of HATU (56.22 mg, 147.86 μmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was lyophilized to get crude product which was purified by Prep-HPLC to afford 3-[7-[2-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-2,8-diazaspiro[4.5]decan-8-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 159 (35 mg, 30% yield, trifluoroacetic acid salt) as an off-white solid. LCMS (ESI): m/z 1037.72 [M+H]⁺. Prep-HPLC method: [Column: X-bridge C18, 5 μm (150mmX19mm), MOBILE Phase A: 0.1% TFA in water, B: acetonitrile, Gradient (T%B):0/15, 2/15, 10/40, 14/45, Flow Rate: 18mL/min Sample, Diluent: Acetonitrile+Water+THF]. ¹H NMR (400 MHz, DMSO-d6): δ 10.9 (s, 1H), 10.55 (bs, 1H), 9.95 (s, 1H),9.22 (s, 1H), 7.79–7.75 (m, 1H), 7.60– 7.57 (m, 1H), 7.39–7.33 (m, 3H), 7.04–7.00 (m, 2H), 6.79 (s, 1H), 5.7-5.5 (m, 1H), 5.49–5.18 (m, 2H), 4.51-4.31 (m, 7H), 4.22 (m, 3H), 4.00–3.65 (m, 6H), 3.6 (m, 2H), 3.33–3.31 (m, 2H), 3.15 (m, 2H), 2.81-2.61 (m, 2H), 2.54 (m, 3H), 2.40–2.37 (m, 4H), 2.19–2.13 (m, 5H), 1.90– 1.85 (m, 5H), 0.71 (t, J = 7.2 Hz, 3H) ppm. Synthesis 165: Synthesis of 3-[7-[2-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-2- azaspiro[5.5]undecan-9-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 160): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (40 mg, 56.33 μmol, hydrochloric acid salt) and 3-[7-(2-azaspiro[5.5]undecan-9-yl)-1-methyl-indazol-3- yl]piperidine-2,6-dione 2 (19.42 mg, 45.06 μmol, hydrochloric acid salt) in N,N- dimethylformamide (1 mL) was added DIPEA (21.84 mg, 168.98 μmol) and HATU (32.13 mg, 84.49 μmol) at 0 °C. The resulting reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was lyophilized to get crude which was purified by Prep-HPLC method to afford 3-[7-[2-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-2-azaspiro[5.5]undecan-9-yl]-1-methyl- indazol-3-yl]piperidine-2,6-dione Compound 160 (10 mg, 16% yield) as an off white solid. LCMS (ESI): m/z 1050.89 [M+H]⁺. Prep-HPLC method: Column/dimensions: x-select C18m (19*250*5 μ), Mobile phase A: 10mm Ammonium acetate in water, Mobile phase B: 100% acetonitrile, Gradient (Time%B): 0/10, 2/20, 13.5/85, Flow rate: 18mL/min, Solubility: Water+Acetonitrile. ¹H NMR (400 MHz, DMSO-d6): δ 10.85 (m, 1H), 9.93 (s, 1H), 9.20 (s, 1H), 7.76–7.54 (m, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.36–7.30 (m, 2H), 7.25 (d, J = 6.8 Hz, 1H), 7.06–6.91 (m, 1H), 6.91–6.67 (m, 2H), 5.41–4.91 (m, 3H), 4.46–4.41 (m, 2H), 4.42–4.21 (m, 2H), 4.20–4.02 (m, 5H), 4.00–3.40 (m, 4H), 3.19–2.98 (m, 4H), 2.89–2.60 (m, 2H), 2.45–2.32 (m, 4H), 2.27–1.93 (m, 6H), 1.91–1.69 (m, 7H), 1.71–1.49 (m, 4H), 1.48–1.02 (m, 5H), 0.72– 0.53 (m, 3H) ppm. Synthesis 166: Synthesis of 3-(7-(2-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-2,9- diazaspiro[5.5]undecan-9-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound 161):

To a solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (65 mg, 91.53 μmol, HCl salt) and 3-[7-(2,9-diazaspiro[5.5]undecan-9-yl)-1-methyl-indazol-3-yl]piperidine-2,6-dione 1 (31.63 mg, 73.22 μmol, HCl salt) in N,N-dimethylformamide (1 mL), were added HATU (52.20 mg, 137.30 μmol) and N,N-diisopropylethylamine (296.80 mg, 2.30 mmol, 0.4 mL) and stirred at room temperature for 16 hours. The crude mixture was the lyophilized to obtained the crude product which was purified by preparative HPLC to afford 3-[7-[2-[5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-2,9-diazaspiro[5.5]undecan-9-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 161 (19 mg, 19 % yield) as an off-white solid. LC-MS (ES⁺): m/z 1051.94 [M+H]⁺. Prep-HPLC method: Column/dimensions: X-BRIDGE C18 (19*150)5μ; Mobile phase A :10 mM ammonium acetate in water; Mobile phase B : acetonitrile Gradient (Time/%B): 0/10, 2/10, 13/18; Flow rate: 18 mL/min; Solubility: Acetonitrile+THF+Water; ¹H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 10.03 (s, 1H), 9.19 (s, 1H), 7.77-7.31 (t, J = 8.4 Hz ,1H), 7.38-6.96 (m, 5H), 6.67-6.51 (m, 2H), 5.19-5.49 (m, 3H), 4.34-4.13 (m, 11H), 3.85-3.32 (m, 4H), 3.09- 2.82 (m, 8H), 2.67-2.49 (m, 4H), 2.33 (bs, 2H), 2.17-2.08 (m, 5H), 1.83-1.79 (m, 5H), 1.57-1.49 (m, 8H), 0.72 (t, d, J = 6.8 Hz, 3H) ppm. Synthesis 167: Synthesis of 3-[6-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 162)

O NH O N O N N N N N F N Et N N N O N F OH F Compound 162 To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (70 mg, 98.57 μmol, hydrochloric acid salt) and 3-[1-methyl-6-[1-(4-piperidylmethyl)-4-piperidyl]indazol-3- yl]piperidine-2,6-dione 2 (36.28 mg, 78.86 μmol, hydrochloric acid salt) in N,N- dimethylformamide (1 mL) was added DIPEA (0.05 mL,295.71 μmol ) and HATU (56.22 mg, 147.86 μmol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was lyophilized to get crude compound which was purified by prep-HPLC to afford 3-[6-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]methyl]-4-piperidyl]-1- methyl-indazol-3-yl]piperidine-2,6-dione Compound 162 (20 mg, 16% yield, trifluoroacetic acid salt ) as an off-white solid. LCMS (ESI): m/z 1079.83 [M+H]⁺. Prep-HPLC method: [Column: X-bridge C18, 5 μm (250mm x 19mm), MOBILE Phase A: 0.1% TFA in water, B: acetonitrile Gradient (T%B): 0/20, 2/25, 10/60, 13/60, Flow Rate: 18 mL/min Sample Diluent: Acetonitrile+Water+THF]. ¹H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 10.65 (bs, 1H), 10.97 (s, 1H), 9.27 (s, 1H),7.80–7.69 (m, 1H),7.66 (d, J = 8.4 Hz, 1H),7.40–7.34 (m, 3H), 7.05– 6.99 (m, 1H) 6.69 (s, 1H), 5.70–5.49 (m, 1H), 5.38–5.15 (m, 2H), 4.78–4.30 (m, 9H), 4.00 (s, 3H), 3.91–3.60 (m, 5H), 3.21–2.90 (m, 8H), 2.81 (m, 1H), 2.65–2.51 (m, 3H), 2.41–2.32 (m, 5H), 2.25–2.15 (m, 6H), 2.14–1.99 (m, 4H), 1.93–1.75 (m, 2H), 1.29–1.05 (m, 2H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 168: Synthesis of 3-[7-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 163): To a stirred solution of 3-[1-methyl-7-[1-(4-piperidylmethyl)-4-piperidyl]indazol-3- yl]piperidine-2,6-dione A-7 (36.28 mg, 78.86 μmol, hydrochloric acid salt) in N,N- dimethylformamide (1.2 mL) at 0 °C was added DIPEA (51.51 μL,295.71 μmol) followed by addition of HATU (56.22 mg, 147.86 μmol) and 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 1 (70 mg, 98.57 μmol, hydrochloric acid salt). The resulting reaction mixture was stirred at room temperature for 12 h h i i l hili d btained crude, which was purified by prep-HPLC to afford 3-[7-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 163 (10 mg, 8% yield, trifluoroacetic acid salt) as an off-white solid. LCMS (ESI): m/z 1079.95 [M+H]⁺. Prep-HPLC method: [Column: X-BRIDGE C18, 5 μm (100 mm x 19 mm), Mobile Phase A: 0.1% TFA in water, Mobile phase B: acetonitrile, Gradient (T%B): 0/10, 2/15, 9/53, 9.1/100, 12/100, 12.1/10, 15/10, Flow Rate: 18mL/min, Sample Diluent: Acetonitrile+ water+ THF]. ¹H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1H), 9.97 (s, 1H), 9.27 (s, 1H), 7.80–7.75 (m, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.39–7.34 (m, 2H), 7.23–6.98 (m, 3H), 6.69 (s, 1H), 5.68–5.52 (m, 1H), 5.36–5.18 (m, 2H), 4.75–4.68 (m, 1H), 4.62–4.33 (m, 8H), 4.25 (s, 3H), 3.91–3.62 (m, 7H), 3.24–3.04 (m, 6H), 2.81–2.56 (m, 5H), 2.42–2.28 (m, 4H), 2.22–2.01 (m, 10H), 1.96–1.74 (m, 2H), 1.26–1.13 (m, 2H), 0.70 (t, J = 7.6 Hz, 3H) ppm. Synthesis 169: Synthesis of 1-[6-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (Compound 164):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (70 mg, 98.57 μmol, hydrochloric acid salt) and 1-[1-methyl-6-[1-(4-piperidylmethyl)-4-piperidyl]indazol-3- yl]hexahydropyrimidine-2,4-dione 2 (36.35 mg, 78.86 μmol, hydrochloric acid salt) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (38.22 mg, 295.71 μmol) followed by addition of HATU (56.22 mg, 147.86 μmol). The reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was lyophilized to get crude which was purified by prep HPLC to afford 1-[6-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]methyl]-4- piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione Compound 164 (13 mg, 10% yield, trifluoroacetic acid salt) as an off-white solid. LC-MS (ES⁺): m/z 1080.84 [M+H]⁺. Prep- HPLC Method: Column: X-bridge C18, 5 Âμm (150 mm x 19mm), Mobile Phase A: 0.1% TFA in water, Mobile Phase B: acetonitrile, Gradient (T%B): 0/15, 2/25, 7/48, Flow Rate: 18mL/min, Sample Diluent: Acetonitrile+Water+THF. ¹H NMR (400 MHz, DMSO-d6): δ 10.87 (bs, 1H), 10.55 (s, 1H), 9.97 (s, 1H), 9.27 (s, 1H), 8.99 (bs, 1H), 7.78–7.74 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.40–7.34 (m, 3H), 6.69 (s, 1H), 5.65–5.20 (m, 3H), 4.59–4.51 (m, 4H), 4.49–4.36 (m, 4H), 3.98 (s, 3H), 3.90 (t, J = 6.4 Hz, 2H), 3.83–3.64 (m, 5H), 3.21–3.09 (m, 4H), 3.07–2.89 (m, 3H), 2.75 (t, J = 6.4 Hz, 3H), 2.59 (m, 1H), 2.46–2.46 (m, 4H), 2.29–2.12 (m, 5H), 2.10–1.98 (m, 5H), 1.90–1.82 (m, 2H), 1.23–1.17 (m, 2H), 0.70 (t, J = 7.2 Hz, 3H). Synthesis 170: Synthesis of 1-[7-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (Compound 165) To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (70 mg, 98.57 μmol, hydrochloric acid salt) and 1-[1-methyl-7-[1-(4-piperidylmethyl)-4-piperidyl]indazol-3- yl]hexahydropyrimidine-2,4-dione 2 (36.35 mg, 78.86 μmol, hydrochloric acid salt ) in N,N- dimethylformamide (1 mL) at 0 °C was added DIPEA (38.22 mg, 295.71 μmol) followed by addition of HATU (5622 14786 l) d th ti i t as allowed to stir at room temperature for 16 hours. The reaction mixture was lyophilized to get crude compound which was purified by prep-HPLC to afford 1-[7-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-4-piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4- dione Compound 165 (29 mg, 23% yield, formic acid salt) as an off-white solid. LCMS (ESI): m/z 1081 [M+H]⁺. Prep-HPLC method: [Column: X-BRIDGE C18, 5 μm (150mmX19mm) Mobile Phase A: 10 mM Ammonium acetate in water, B: Acetonitrile, Gradient (T%B): 0/10,2/15,12.20/77,12.30/98,15/98,15.10/10,17.50/10, Flow Rate: 18mL/min, Sample Diluent: Acetonitrile+ water+ THF]. ¹H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 10.42–9.88 (bs, 1H), 9.20 (s, 1H), 7.76–7.73 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.37–7.25 (m, 3H), 7.06 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.56 (s, 1H), 5.35–5.13 (m, 3H), 4.63–4.25 (m, 6H), 4.21– 4.05 (m, 5H), 3.86 (t, J = 6.8 Hz, 2H), 3.13–2.95 (m, 8H), 2.84–2.67 (m, 4H), 2.32 (bs, 3H), 2.22–1.97 (m, 9H), 1.91–1.69 (m, 8H), 1.11–0.97 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 171: Synthesis of 3-[6-[4-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-1-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 166):

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (70 mg, 98.57 μmol, hydrochloric acid salt) and 3-[1-methyl-6-[4-(4-piperidylmethyl)-1-piperidyl]indazol-3- yl]piperidine-2,6-dione 2 (36.28 mg, 78.86 μmol, hydrochloric acid salt) in N,N- dimethylformamide (2 mL) was added DIPEA (38.22 mg, 295.71 μmol) and HATU (56.22 mg, 147.86 μmol) and the reaction mixture was stirred at the room temperature for 16 hours. The reaction mixture was concentrated under the reduced pressure and the crude obtained was purified by Prep-HPLC to afford 3-[6-[4-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-1-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 166 (8 mg, 7 % yield ) as an off-white solid. LC-MS (ESI): m/z 1079.88 [M+H] ⁺; Prep-HPLC method: Column/dimensions: X-BRIDGE-C18; 250x19mm; 5u Mobile phase A: 10 mM ammonium acetate in water Mobile phase B: acetonitrile Gradient (Time/%B): 0/10,2 /30,11/65,13/65, Flow rate: 18mL/min Solubility: WATER+ACN+THF; ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (bs, 1H), 10.45 (bs, 1H), 9.20 (s, 1H), 7.77-7.73 (m, 2H), 7.46 (d, 1H), 7.36-7.33 (m, 2H), 7.01 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 9.2 Hz, 1H), 6.81 (s, 1H), 6.56 (s, 1H), 5.45-5.13 (m, 3H), 4.70-4.32 (m, 7H) , 4.12-4.05 (m, 2H), 3.87 (s, 3H), 3.76 (m, 2H), 3.10-3.01 (m, 4H), 2.83 (m, 1H), 2.72- 2.69 (m, 2H), 2.63-2.60 (m, 2H), 2.30 (s, 2H), 2.21–1.99 (m, 5H), 1.84-1.69 (m, 12H), 1.55 (bs, 1H), 1.35-1.17 (m, 2H), 1.05 (m, 2H), 0.72 (t, J = 7.2 Hz, 3H). Synthesis 172: Synthesis of 3-[7-[4-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-1-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 167): To a solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (70 mg, 98.57 μmol, HCl salt) and 3-[1-methyl-7-[4-(4-piperidylmethyl)-1-piperidyl]indazol-3-yl]piperidine-2,6-dione 2 (36.28 mg, 78.86 μmol, HCl salt) in N,N-dimethylformamide (1 mL) were added HATU (56.22 mg, 147.86 μmol) and N,N-diisopropylethylamine (296.80 mg, 2.30 mmol, 0.4 mL), the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was the lyophilized to obtain crude product which was purified by Prep HPLC method to afford 3-[7-[4-[[1-[5-[7- (8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]methyl]-1-piperidyl]-1- methyl-indazol-3-yl]piperidine-2,6-dione Compound 167 (35 mg, 29 % yield, TFA salt) as an off-white solid. LCMS (ESI): m/z 1079.88 [M+H]⁺. Preparative HPLC method: Column/dimensions: X-BRIDGE C18 (19 *100) 5μ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/15, 15/75; Flow rate: 18 mL/min; Solubility: Water+ acetonitrile+ THF.¹H NMR (400 MHz, DMSO-d₆): δ 10.87 (s, 1H), 10.70 (s, 1H), 9.91 (s, 1H), 9.29 (s, 1H), 7.79-75 (m, 1H), 7.38-7.33 (m, 2H), 7.20-6.95 (m, 3H), 6.66 (s, 1H), 5.53-5.51 (m, 1H), 5.40-5.20 (m, 2H), 4.61-4.40 (m, 7H), 4.40-4.30 (m, 2H), 4.23 (s, 3H), 3.90-3.85 (m, 4H), 3.31-3.21 (m, 3H), 3.05-3.15 (m, 2H), 2.65-2.60 (m, 6H), 2.49-2.30 (m, 5H), 2.18-2.20 (m, 5H), 1.81-1.71 (m, 5H), 1.50 (bs, 1H), 1.40-1.37 (m, 2H), 1.23 (bs, 2H), 1.10-1.07 (m, 2H), 0.72-0.68 (t, J = 8.4, 3H). Synthesis 173: Synthesis of 1-[6-[4-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-1-piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (Compound 168):

To a solution 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (80 mg, 112.65 μmol, HCl salt) and 1-[1-methyl-6-[4-(4-piperidylmethyl)-1-piperidyl]indazol-3-yl]hexahydropyrimidine-2,4- dione 2 (74.19 mg, 160.93 μmol, trifluoromethanesulfonic acid salt) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (296.80 mg, 2.30 mmol, 0.4 mL) and HATU (91.79 mg, 241.40 μmol), the resulting mixture was stirred at room temperature for 16 hours. The crude mixture was then lyophilized to obtained crude product, which was purified by prep HPLC to afford 1-[6-[4-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]methyl]-1- piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione Compound 168 (60 mg, 30 % yield, TFA salt) as an off-white solid. LC-MS (ESI): m/z 1052.83 [M+H]⁺. Preparative HPLC method: Column / dimensions: X-SELECT C18, 5 μm (100mmX19mm); Mobile phase A: 0.1% TFA in water; Mobile phase B: 100% Acetonitrile; Gradient (Time/%B): 0/10, 2/15, 8.35/49, 8.50/98, 11/98, 11.10/10, 13.50/10; Flow rate: 18 mL/min; Solubility : Water+Acetonitrile+THF].¹H NMR (400 MHz, DMSO-d₆): δ 10.60 (s, 1H), 10.50 (s, 1H), 10.01 (s, 1H), 9.28 (s, 1H), 7.79-7.75 (m, 1H), 7.46-7.44 (d, J = 8 Hz, 3H), 7.38-7.33 (m, 2H), 7.20- 6.85 (m, 2H), 6.66 (s, 1H), 5.30-5.22 (m, 1H), 5.35-5.19 (m, 2H), 5.40-5.20 (m, 2H), 3.90-3.83 (m, 8H), 4.61-4.44 (m, 8H), 3.90-3.50 (m, 9H), 3.33-3.23 (m, 1H), 2.75-2.67 (m, 4H), 2.67-2.66 (m, 2H), 2.36-2.32 (m, 4H), 1.78-1.70 (m, 4H), 1.60-1.50 (m, 1H), 1.28-1.18 (m, 4H), 1.10-0.90 (m, 2H), 0.72-0.68 (t J = 8 H 3H) Synthesis 174: Synthesis of 1-[7-[4-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-1-piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (Compound 169): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 1 ( (70 mg, 98.57 μmol, hydrochloric acid salt) and 1-[1-methyl-7-[4-(4-piperidylmethyl)-1-piperidyl]indazol-3- yl]hexahydropyrimidine-2,4-dione 2 (42.47 mg, 78.86 μmol, trifluoroacetic acid salt) in N,N- diisopropylethylamine (1.5 mL) at 0 °C was added DIPEA (38.22 mg, 295.71 μmol) followed by addition HATU (56.22 mg, 147.86 μmol). The resulting reaction mixture was allowed to stir at room temperature and stirred for 12 hours. The reaction mixture was lyophilized to get crude which was purified by Prep HPLC to afford 1 [7 [4 [[1 [5 [7 (8 ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-4-piperidyl]-methyl]-1-piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4- dione Compound 169 (14 mg, 13% yield) as an off-white solid. LCMS (ESI): m/z 1080.86 [M+H]⁺. Prep-HPLC method: Column: X-SELECT C18, 5 μm (100mm X 19mm), Mobile Phase A: 0.1% FA in water, Mobile Phase B: acetonitrile, Gradient (T%B): 0/25, 2/35, 15/95, 15.10/98, 17.50/98, 17.60/10, 20/10, Flow Rate: 18mL/min, Sample Diluent: Acetonitrile+Water+THF. ¹H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 9.95 (bs, 1H), 9.20 (s, 1H), 7.78–7.74 (m, 1H), 7.37–7.32 (m, 2H), 7.27 (t, J = 4.4 Hz, 1H), 6.99 (d, J = 4.8 Hz, 3H), 6.56 (s, 1H), 5.39 .10 (m, 3H), 4.65–4.20 (m, 9H), 4.19–4.05 (m, 2H), 3.87 (t, J = 6.4 Hz, 1H), 3.21 (m, 2H), 3.95–3.11 (m, 4H), 2.83 (m, 1H), 2.75 (t, J = 6.8 Hz, 2H), 2.69 (m, 2H), 2.35 (m, 2H), 2.19–2.09 (m, 2H), 2.05–1.98 (m, 2H), 1.90–1.80 (m, 5H), 1.78–1.65 (m, 6H), 1.55 (m, 2H), 1.41–1.35 (m, 2H), 1.23 (s, 1H), 1.05–1.03 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 175: Synthesis of 1-(7-(4-((1-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2- carbonyl)piperidin-4-yl)methyl)piperidin-1-yl)benzo[d]isoxazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (Compound 170)

To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (60 mg, 84.49 μmol, hydrochloric acid) and 1-[6-[1-(4-piperidylmethyl)-4-piperidyl]-1,2-benzoxazol-3- yl]hexahydropyrimidine-2,4-dione (35.52 mg, 67.59 μmol, trifluoroacetic acid) in N,N- diisopropylethylamine (1 mL) at 0 °C was added DIPEA (32.76 mg, 253.47 μmol, 44.15 μL) followed by addition of HATU (48.19 mg, 126.73 μmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was lyophilized to get crude compound which was purified by prep-HPLC to afford 1-[6-[1-[[1-[5-[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-4-piperidyl]methyl]-4-piperidyl]-1,2-benzoxazol-3-yl]hexahydropyrimidine-2,4- dione Compound 170 (15 mg, 13.36 μmol, 15.81% yield, 95.03% purity) as an off-white solid. LCMS (ESI): m/z 1067.88 [M+H]⁺; Prep-HPLC Condition: Column:X-BRIDGE C18, 5 μm (250mmX19mm) , Mobile Phase A: 10 mM Ammonium acetate in water, B: ACN , Gradient (T%B): 0/10,2/15,12.20/77,12.30/98,15/98,15.10/10,17.50/10 , Flow Rate: 18mL/min Sample , Diluent: ACN+Water+THF. ¹H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 9.98 (bs, 1H) 9.20 (s, 1H), 7.78–7.73 (m, 1H),7.56 (s, 1H), 7.3–7.28 (m, 3H), 7.0 (d, J = 2 Hz, 1H), 6.56 (s, 1H), 5.36–5.13 (m, 3H), 4.61–4.25 (m, 6H), 4.16–4.05 (m, 4H), 3.13–2.99 (m, 7H), 2.78–2.65 (m, 5H), 2.4-2.34 (m, 2H), 2.3–2.1(m, 5H), 2.09–1.93 (m, 4H),1.91–1.75 (m, 8H), 1.45 (m, 6H), 1.02 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 176: Synthesis of 3-[6-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-4-piperidyl]-1,2-benzoxazol-3-yl]piperidine-2,6-dione (Compound 171): To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (70 mg, 98.57 μmol, hydrochloric acid salt) and 3-[6-[1-(4-piperidylmethyl)-4-piperidyl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione 2 (35.25 mg, 78.86 μmol, hydrochloric acid salt) in N,N- diisopropylethylamine (1.5 mL) at 0 °C was added DIPEA (38.22 mg, 295.71 μmol) followed by addition of HATU (56.22 mg, 147.86 μmol). The reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was lyophilized to obtained crude which was purified prep-HPLC method to afford 3-[6-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo-[1,5-a][1,4]diazepine-2- carbonyl]-4-piperidyl]methyl]-4-piperidyl]-1,2-benzoxazol-3-yl]piperidine-2,6-dione Compound 171 (23 mg, 20% yield, formic acid salt) as an off-white solid. LC-MS (ES⁺): m/z 1066.85 [M+H]⁺. Prep-HPLC Method: Column: X-BRIDGE C18, 5 μm (150mm X 19mm), Mobile Phase A: 10 μM Ammonium acetate in water, Mobile Phase B: 0.1% FA in acetonitrile, Gradient (T% B): 0/10, 2/10, 11/50, 11.1/98, 13/98,13.1/10, 15/10, Flow Rate: 18mL/min, Sample Diluent: Acetonitrile+ water+ THF]; ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (bs, 1H), 10.45–9.92 (bs, 1H), 9.20 (s, 1H), 7.77–7.73 (m, 2H), 7.60 (s, 1H), 7.36–7.29 (m, 3H), 7.01 (d, J = 2.4 Hz, 1H), 6.56 (s, 1H), 5.38–5.13 (m, 3H), 4.64–4.24 (m, 6H), 4.16–4.05 (m, 2H), 3.12– 2.92 (m, 6H), 2.85–2.68 (m, 4H), 2.63–2.56 (m, 1H), 2.46–2.28 (m, 5H), 2.21–1.95 (m, 10H), 1.87–1.66 (m, 11H), 1.08–0.96 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H) ppm. Synthesis 177: Synthesis of 3-[7-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-4-piperidyl]-1,2-benzoxazol-3-yl]piperidine-2,6-dione (Compound 172): O H N _O O N N O N N N F N Et N N N O N F OH F Compound 172 To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-7 (70 mg, 98.57 μmol, hydrochloric acid salt) and 3-[7-[1-(4-piperidylmethyl)-4-piperidyl]-1,2-benzoxazol-3- yl]piperidine-2,6-dione 2 (35.25 mg, 78.86 μmol, hydrochloric acid salt) in N,N- diisopropylethylamine (1.5 mL) at 0 °C was added DIPEA (38.22 mg, 295.71 μmol) followed by addition of HATU (56.22 mg, 147.86 μmol). The resulting reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was lyophilized to get crude compound which was purified by Prep-HPLC method to afford 3-[7-[1-[[1-[5-[7-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-4-piperidyl]methyl]-4-piperidyl]-1,2-benzoxazol-3-yl]piperidine-2,6-dione Compound 172 (16 mg, 14% yield, trifluoroacetic acid salt) as an off-white solid. LCMS (ESI): m/z 1066.87 [M+H]⁺. Prep-HPLC method: Column/dimensions: XSELECT C18 (10*250mm) 5 μm, Mobile phase A: 0.1% TFA in water, Mobile phase B: acetonitrile, Gradient (Time/%B): 0/20, 2/20, 10/60, 10.1/100, 12/100, 12.1/20, Flow rate: 7mL/min, Solubility: Acetonitrile+ water+ THF.¹H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 10.69 (bs, 1H), 9.95 (s, 1H), 9.27 (s, 1H), 9.07 (bs, 1H), 7.79–7.75 (m, 2H), 7.50 (d, J = 7.2 Hz 1H), 7.40–7.34 (m, 1H), 6.99 (d, J = 2.8 Hz, 1H), 6.69 (s, 1H), 5.69–5.51 (m, 1H), 5.35–5.15 (m, 2H), 4.65–4.30 (m, 9H), 3.91– 3.61 (m, 6H), 3.50 (m, 2H), 3.18 (m, 3H), 3.05 (s, 2H), 3.81–3.71 (m, 2H), 3.60–2.55 (m, 2H), 2.38 (m, 4H), 2.30–2.15 (m, 6H), 2.14–2.00 (m, 5H), 1.90–1.75 (m, 2H), 1.28–1.10 (m, 2H), 0.70 (t, J = 7.2 Hz, 3H) ppm. Synthesis 178: Synthesis of [5-[2-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-7-(3- morpholinopropoxy)pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (Compound 329):

Step-1: The solution of [1-[(dimethylamino)methyl]cyclopropyl]methanol 2 (80.82 mg, 625.58 μmol) in tetrahydrofuran (5 mL) was cooled to 0 ^oC and NaH ^60% dispersion in oil, 25.02 mg, 1040 μmol) was added under argon atmosphere. Benzyl 4-[5-(2,7-dichloro-8-fluoro-pyrido[4,3- d]pyrimidin-4-yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1- carboxylate A-8 (250.00 mg, 417.05 μmol) was added and the reaction mixture was allowed to stir at room temperature for 6 hours. The reaction was then quenched with cold water, and purified by column chromatography to afford benzyl 4-[5-[7-chloro-2-[[1- [(dimethylamino)m ]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate 3 (210 mg, 51% yield) as a light yellow semi-solid compound. LCMS (ES+): m/z 692.65 [M+H]⁺. Step-2: To a solution of benzyl 4-[5-[7-chloro-2-[[1- [(dimethylamino)methyl]cyclopropyl]methoxy]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate 3 (210.00 mg, 303.39 μmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane 4 (163.93 mg, 455.08 μmol) in mixture of water (0.8 mL) and tetrahydrofuran (4 mL) was added K₃PO₄ (128.80 mg, 606.78 μmol) and degassed with argon gas for 10 minutes. CataCXium A Pd G3 (22.09 mg, 30.34 μmol) was then added and the resulting reaction mixture was subjected to microwave irradiation at 100 °C for an hour. The reaction mixture was concentrated to afford the crude product, which was purified by column chromatography to afford benzyl 4-[5-[2-[[1-[(dimethylamino)methyl]cyclopropyl]methoxy]-7- [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate 5 (190 mg, 51% yield) as a yellow sticky compound. LCMS (ES+): m/z 890.54 [M+H]^+. Step-3: To a solution of benzyl 4-[5-[2-[[1-[(dimethylamino)methyl]cyclopropyl]methoxy]-7- [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate 5 (190.00 mg, 213.49 μmol) in a mixture of methanol (2 mL) and ethyl acetate (2 mL) was added 10% palladium on carbon (190 mg, 1790 μmol) and stirred at room temperature for 2 hours under hydrogen (1 atm pressure). The reaction mixture was filtered, washed with 1:1 methanol: ethyl acetate, and the filtrate was concentrated under reduced pressure to afford [5-[2-[[1- [(dimethylamino)methyl]cyclopropyl]methoxy]-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone 6 (170 mg, 71% yield) as a light brown sticky compound. LCMS data: m/z 756.95 [M+H]⁺. Step-4: To a solution of [5-[2-[[1-[(dimethylamino)methyl]cyclopropyl]methoxy]-7-[8-ethyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone 6 (170.00 mg, 224.91 μmol) in dichloromethane (6 mL) was added 4M HCl in 1,4-dioxane (0.2 mL, 224.91 μmol) at 0 °C and the reaction mixture was stirred at 0 °C for 15 minutes. The reaction mixture was concentrated under reduced pressure to get the crude product, which was triturated with diethyl ether to afford [5-[2-[[1-[(dimethylamino)methyl]cyclopropyl]methoxy]-7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo-[1,5- a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone 7 (120 mg, 56% yield) as a light brown solid. LCMS (ES+): m/z 712.76 [M+H]⁺. Step-5: To a stirred solution of [5-[2-[[1-[(dimethylamino)methyl]cyclopropyl]methoxy]-7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone 6 (120.00 mg, 160.37 μmol, hydrochloric acid salt) in N,N-dimethylformamide (2 mL) was added N,N- diisopropylethylamine (0.139 mL, 801.86 μmol) and 2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]-1-piperidyl]acetic acid 7 (51.57 mg, 112.26 μmol, trifluoroacetic acid salt) at 0 °C followed by HATU (91.47 mg, 240.56 μmol). The reaction mixture was stirred at room temperature for an hour. The reaction mixture was concentrated under reduced pressure to get crude, which was purified by prep-HPLC to afford product 3-[4-[1-[2-[4-[5-[2-[[1- [(dimethylamino)methyl]cyclopropyl]methoxy]-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]anilino]piperidine-2,6-dione Compound 329 (27 mg, 15% yield) as an off-white solid. LCMS (ESI): m/z 1039.96 [M+H]⁺. Preparative HPLC method: Column/dimension: X-BRIDGE C18 (19*150)5μ Mobile phase A: 10 mM Ammonium acetate in water Mobile phase B: 100% acetonitrile Gradient (Time /%B):0/10, 2/15, 17/70 Flow rate: 18mL/min Solubility: Water+ acetonitrile+ THF.¹H NMR (400 MHz, DMSO- d6): δ 10.82–10.58 (bs, 1H), 9.18 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.37–7.26 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 6.8 Hz, 2H), 6.67 (s, 1H), 6.59 (d, J = 8.0 Hz, 2H), 5.63 (d, J = 7.6 Hz, 1H), 5.33–5.16 (m, 2H), 4.53 (d, J = 5.6 Hz, 2H), 4.40–4.22 (m, 5H), 4.05–3.91 (m, 2H), 3.68–3.52 (m, 6H), 3.16 (bs, 2H), 2.93–2.86 (m, 2H), 2.76–2.58 (m, 2H), 2.38–2.22 (m, 4H), 2.17–2.04 (m, 5H), 1.92–1.77 (m, 9H), 1.62–1.48 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H), 0.63 (d, J = 6.2 Hz, 2H), 0.40 (d, J = 5.6 Hz, 2H). Synthesis 179: Synthesis of 3-((4-(1-(2-(4-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)piperazin-1-yl)-2- oxoethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (Compound 203):

Step-1: A solution of [1-(morpholinomethyl)cyclopropyl]methanol (1) (171.40 mg, 1.00 mmol) in tetrahydrofuran (8 mL) was cool to 0 ^oC and added NaH ^60% dispersion in oil ^ (40.03 mg, 1.67 mmol) under argon atmosphere. Benzyl 4-[5-(2,7-dichloro-8-fluoro-pyrido[4,3- d]pyrimidin-4-yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1- carboxylate (A-8) (400 mg, 667.29 μmol) was then added after 5 minutes, and the reaction mixture to was allowed to stir at room temperature for three hours. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was filtered through celite, then the filtrate was extracted into 10% methanol/ dichloromethane (2 X 10 mL). Collected organic layer was washed with saturated brine solution (5 mL). The organic layer was dried over with anhydrous Na₂SO₄, filtered, and then concentrated to afford the crude product. Then the crude was purified by column chromatography using silica gel (100-200 mesh). The desired product was eluted at 1% methanol/dichloromethane to afford benzyl 4-[5-[7-chloro-8- fluoro-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (2) (240 mg, 269.97 μmol, 40.46% yield, 82.59% purity, no salt) as a brown gummy. LCMS (ES+): m/z 734.48 [M+H]⁺; Retention time (min): 0.70. Step-2: To a solution of benzyl 4-[5-[7-chloro-8-fluoro-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (2) (240 mg, 326.88 μmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (3) (176.63 mg, 490.32 μmol) in mixture of water (0.8 mL) and tetrahydrofuran (4 mL) was added potassium phosphate tribasic (138.77 mg, 653.76 μmol) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes then cataCXium-A-Pd-G3 (23.81 mg, 32.69 μmol) was added, and the resulting reaction mixture was stirred at 100 °C for an hour in a microwave apparatus. The progress of the reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was filtered through celite using ethyl acetate (2 x 50 mL), then filtrate was extracted into 10% methanol/dichloromethane (2 x 50 mL). The collected organic layer was washed with saturated brine solution (20 mL). The organic layer was dried over with anhydrous Na₂SO₄, filtered and then concentrated. Thus the obtained crude product was purified by silica gel (100 -200 mesh) column chromatography by eluting at 3% methanol/dichloromethane to afford benzyl 4-[5-[7- [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (4) (230 mg, 155.57 μmol, 47.59% yield, 63.04% purity, no salt) as a yellow solid. LCMS (ES+): m/z 932.78 [M+H]⁺; Retention time (min): 0.78. Step-3: To a solution of benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (4) (230 mg, 246.78 μmol) in methanol (2 mL)and ethyl acetate (2 mL) was added 10% palladium on carbon wet (230.00 mg, 2.16 mmol), the reaction mixture was stirred at room temperature for 6 hours under hydrogen bladder pressure, while monitored by TLC and LCMS. After completion of starting material, the reaction mixture was filtered through celite bed and washed with methanol:ethyl acetate (1:1, 20 mL x 3), concentrated under reduced pressure to afford [5-[7-[8- ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (5) (160 mg, 122.24 μmol, 49.54% yield, 60.96% purity, no salt) as a light green solid. LCMS (ES+): m/z 798.49 [M+H]⁺; Retention time (min): 1.44. Step-4: To a solution of [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[1-(morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (5) (230 mg, 288.26 μmol) in dichloromethane (0.5 mL) was added HCl ^4.0 M in 1,4-dioxane ^ (31.53 mg, 864.78 μmol, 1 mL) at 0 °C and the reaction mixture was stirred at 0 °C for 15 minutes. The reaction mixture was concentrated in vacuo to get the crude product, which was triturated with diethyl ether (2 X 3 mL) to afford [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (6) (170 mg, 110.85 μmol, 38.45% yield, 51.53% purity, hydrochloric acid) as a light yellow solid. LCMS (ES+): m/z 754.68 [M+H]⁺; Retention time (min): 0.51. Step-5: To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (6) (130 mg, 164.49 μmol, hydrochloric acid) in N,N-dimethylformamide (2 mL) was added DIPEA (106.30 mg, 822.47 μmol, 143.26 μL) and 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]-1-piperidyl]acetic acid (C-21) (66.69 mg, 129.63 μmol, trifluoroacetic acid) at 0 °C, followed by addition of HATU (93.82 mg, 246.74 μmol) at same temperature. The reaction mixture was stirred at 25 °C for an hour. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with ice-cold water (5 mL) to get precipitated solid which was filtered to get crude product. The crude was purified by prep-HPLC to afford product 3-[4-[1- [2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4- piperidyl]anilino]piperidine-2,6-dione (Compound 203) (18 mg, 15.52 μmol, 9.43% yield, 93.20% purity, no salt) as an off-white solid. Column/dimensions: X-BRIDGE C18 (19*250*5μm); Mobile phase A:10 mM Ammonium acetate in water(AQ); Mobile phase B: 100% acetonitrile. Gradient (Time/%B): 0/10,2/10,10/50,13/50; Flow rate: 18 mL/min; Solubility: Acetonitrile+ water+ THF; LCMS (ES+): m/z 1081.53 [M+H]⁺; Retention time (min): 2.56; ¹H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 10.03 (bs, 1H), 9.19 (s, 1H), 7.78– 7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.36–7.29 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.97–6.89 (m, 2H), 6.67 (s, 1H), 6.59 (d, J = 8.4 Hz, 2H), 5.63 (d, J = 7.6 Hz, 1H), 5.33–5.17 (m, 2H), 4.53 (d, J = 5.2 Hz, 2H), 4.41–4.23 (m, 5H), 4.08–3.90 (m, 2H), 3.68–3.55 (m, 4H), 3.53–3.45 (m, 6H), 3.16 (bs, 2H), 2.93–2.85 (m, 2H), 2.77–2.54 (m, 3H), 2.42–2.27 (m, 9H), 2.14–1.93 (m, 4H), 1.90– 1.78 (m, 1H), 1.69–1.48 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H), 0.64 (d, J = 6.2 Hz, 2H), 0.41 (d, J = 5.8 Hz, 2H). Synthesis 180: Synthesis of 3-((4-(1-(2-(4-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-2-((R)-2-methyl-3-morpholinopropoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)piperazin-1-yl)-2- oxoethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (Compound 204):

Step-1: A solution of (2R)-2-methyl-3-morpholino-propan-1-ol (1) (99.61 mg, 625.58 μmol) in tetrahydrofuran (5 mL) was cool to 0 ^oC and NaH ^60% dispersion in oil ^ (25.02 mg, 1.04 mmol) was added under argon atmosphere. Benzyl 4-[5-(2,7-dichloro-8-fluoro-pyrido[4,3- d]pyrimidin-4-yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1- carboxylate (A-8) (250 mg, 417.05 μmol) was added after 5 minutes, and reaction mixture was allowed to attain room temperature. The reaction mixture was stirred at room temperature for 3 hours, while monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was diluted with ice-cold water (20 mL), which was then extracted into 10% methanol/dichloromethane (2 x 50 mL). The collected organic layer was washed with saturated brine solution (10 mL). The organic layer was dried over with anhydrous Na2SO4, filtered and then concentrated to afford the crude product. Then the crude was purified by column chromatography using silica gel (100-200 mesh), desired product was eluted at 5% c to afford benzyl 4-[5-[7-chloro-8-fluoro-2-[(2R)-2-methyl-3-morpholino-propoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1- carboxylate (2) (210 mg, 188.19 μmol, 45.12% yield, 64.72% purity, no salt) as a brown gummy. LCMS (ES+): m/z 722.80 [M+H]⁺. Retention time (min): 0.63. Step-2: To a solution of benzyl 4-[5-[7-chloro-8-fluoro-2-[(2R)-2-methyl-3-morpholino- propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazine-1-carboxylate (2) (210 mg, 290.78 μmol) and 2-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3) (157.12 mg, 436.16 μmol) in a mixture of water (0.8 mL) and tetrahydrofuran (4 mL) was added potassium phosphate tribasic (123.44 mg, 581.55 μmol) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes then cataCXium-A-Pd-G3 (21.18 mg, 29.08 μmol) was added and the resulting reaction mixture was stirred at 100 °C for an hour in a microwave apparatus. The progress of the reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was diluted with ice-cold water (20 mL), which was extracted into 10% methanol/dichloromethane (2 x 50 mL). The collected organic layer was washed with saturated brine solution (10 mL). The organic layer was dried over with anhydrous Na₂SO₄, filtered and then concentrated to afford the crude product. Then the crude was purified by column chromatography using silica gel (100 - 200 mesh), desired product was eluted at 5% methanol/dichloromethane to afford benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[(2R)-2-methyl-3-morpholino-propoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (4) (180 mg, 148.93 μmol, 51.22% yield, 76.12% purity, no salt) as a brown gummy. LCMS (ES+): m/z 920.63 [M+H]⁺. Retention time (min): 1.92. Step-3: To a solution of benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[(2R)-2-methyl-3-morpholino-propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (4) (180 mg, 195.65 μmol) in ethyl acetate (2 mL) and methanol (2 mL) was added 10% palladium on carbon wet (180.00 mg, 1.69 mmol), the reaction mixture was stirred at room temperature for 2 hours under hydrogen bladder pressure, while monitored by TLC and LCMS. After completion of starting material, the reaction mixture was filtered through celite bed and washed with methanol:ethyl acetate (1:1, 20 mL x 3), and then concentrated under reduced pressure to afford [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[(2R)-2-methyl-3- morpholino-propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (5) (150 mg, 120.61 μmol, 61.65% yield, 63.19% purity, no salt) as a light yellow solid. LCMS (ES+): m/z 786.82 [M+H]⁺. Retention time (min): 0.62. Step-4: To a solution of [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [(2R)-2-methyl-3-morpholino-propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (5) (150 mg, 190.87 μmol) in dichloromethane (6 mL) was added HCl ^4.0 M in 1,4-dioxane ^ (6.96 mg, 190.87 μmol, 0.1 mL) at 0 °C and the reaction mixture was stirred at 0 °C for 15 minutes. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was concentrated in vacuo to get the crude product, which was triturated with diethyl ether (2 x 2 mL) to afford [5- [7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[(2R)-2-methyl-3-morpholino- propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]- piperazin-1-yl-methanone (6) (140 mg, 105.02 μmol, 55.02% yield, 58.38% purity, hydrochloric acid) as a light yellow solid. LCMS (ES+): m/z 742.94 [M+H]⁺. Retention time (min): 0.47. Step-5: To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[(2R)- 2-methyl-3-morpholino-propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (6) (140 mg, 179.88 μmol, hydrochloric acid) in N,N-dimethylformamide (2 mL) was added DIPEA (116.24 mg, 899.41 μmol, 156.66 μL) and 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetic acid (C21) (82.64 mg, 179.88 μmol, trifluoroacetic acid) at 0 °C, followed by addition of HATU (102.59 mg, 269.82 μmol). The reaction mixture was stirred at 25 °C for an hour. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with ice-cold water (5 mL) to get precipitated solid, which was filtered to get crude product. The crude was purified by prep-HPLC to afford product 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[(2R)-2- methyl-3-morpholino-propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]anilino]piperidine-2,6- dione (Compound 204) (33 mg, 30.06 μmol, 16.71% yield, 97.41% purity, no salt) as an off- white solid. Column/dimensions: X-Bridge C18m (19*100*5 μ); Mobile phase A: 10 mM Ammonium acetate in water; Mobile phase B: 100% acetonitrile; Gradient (Time/%B): 0/10,2/15,12.75/6; Flow rate: 18mL/min; Solubility: WATER+ACN+THF; LCMS (ES+): m/z 1069.60 [M+H]⁺; Retention time (min): 2.52; ¹H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 9.92 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.38–7.31 (m, 2H), 7.01 (d, J = 2.0 Hz, 1H), 6.98–6.90 (m, 2H), 6.68 (s, 1H), 6.59 (d, J = 8.4 Hz, 2H), 5.63 (d, J = 7.6 Hz, 1H), 5.33–5.15 (m, 2H), 4.40–4.23 (m, 3H), 4.18–4.12 (m, 1H), 4.05–3.90 (m, 2H), 3.68–3.48 (m, 10H), 3.16 (bs, 2H), 2.93–2.86 (m, 2H), 2.77–2.54 (m, 3H), 2.42–2.27 (m, 9H), 2.24–2.03 (m, 6H), 1.90–1.78 (m, 3H), 1.71–1.48 (m, 4H), 0.98 (d, J = 6.0 Hz, 3H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 181: Synthesis of 3-((4-(1-(2-(4-(5-(2-((2R)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8- yl)-2-methylpropoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2- carbonyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (Compound 206):

Step-1: A solution of (2R)-2-methyl-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propan-1-ol (1) (115.90 mg, 625.58 μmol) in tetrahydrofuran (5 mL) was stirred and cooled to 0℃, and NaH ^60% dispersion in oil ^ (25.02 mg, 1.04 mmol) was added under argon atmosphere. Benzyl 4-[5-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (A-8) (250 mg, 417.05 μmol) was added after 5 minutes, and reaction mixture was allowed to attain room temperature. The reaction mixture was stirred at room temperature for 2 hours, while monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was diluted with ice-cold water (20 mL), which was extracted into 10% methanol/dichloromethane (2 x 50 mL). The collected organic layer was washed with saturated sodium chloride solution (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and then concentrated to afford the crude product. Then the crude was purified by column chromatography using silica gel (100-200 mesh), desired product was eluted at 7% methanol/dichloromethane to afford benzyl 4-[5-[7-chloro-8-fluoro-2-[(2R)-2- methyl-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (2) (220 mg, 158.89 μmol, 38.10% yield, 54.04% purity, no salt) as a light yellow gummy. LCMS (ES+): m/z 778.84 [M+H]⁺; Retention time (min): 0.67. Step-2: To a solution of benzyl 4-[5-[7-chloro-8-fluoro-2-[(2R)-2-methyl-3-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (2) (220 mg, 294.02 μmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (3) (158.87 mg, 441.03 μmol) in mixture of water (0.8 mL) and tetrahydrofuran (4 mL) was added potassium phosphate tribasic (124.82 mg, 588.04 μmol) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes then cataCXium-A-Pd-G3 (21.41 mg, 29.40 μmol) was added, and the resulting reaction mixture was stirred at 100 °C for an hour in a microwave apparatus. The progress of the reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was diluted with ice-cold water (20 mL), which was extracted into 10% methanol/dichloromethane (2 x 50 mL). The collected organic layer was washed with saturated sodium chloride solution (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and then concentrated to afford the crude product. Then the crude was purified by column chromatography using silica gel (100-200 mesh), desired product was eluted at 6% methanol/dichloromethane to afford benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[(2R)-2-methyl- 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (4) (230 mg, 113.66 μmol, 38.66% yield, 46.75% purity, no salt) as a yellow gummy. LCMS (ES+): m/z 947.05 [M+H]⁺; Retention time (min): 0.82. Step-3: To a solution of benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[(2R)-2-methyl-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1- carboxylate (4) (230 mg, 243.12 μmol) in methanol (2 mL) and ethyl acetate (2 mL) was added 10% palladium on carbon wet (230 mg, 2.16 mmol), the reaction mixture was stirred at room temperature for 2 hours under hydrogen bladder pressure, while monitored by TLC and LCMS. After completion of starting material, the reaction mixture was filtered through celite bed and washed with methanol:ethyl acetate (1:1, 20 mL Xx 3), concentrated under reduced pressure to afford [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[(2R)-2-methyl-3- (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (5) (210 mg, 119.83 μmol, 49.29% yield, 46.33% purity, no salt) as a light yellow gummy. LCMS (ES+): m/z 812.86 [M+H]⁺; Retention time (min): 0.62. Step-4: To a solution of [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [(2R)-2-methyl-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (5) (210 mg, 258.65 μmol) in dichloromethane (8 mL) was added HCl ^40 M in 1,4-dioxane ^ (9.43 mg, 258.65 μmol, 0.2 mL) at 0 °C and the reaction mixture was stirred at 0 °C for 15 minutes. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was concentrated in vacuo to get the crude product, which was triturated with diethyl ether (2 x 3 mL) to afford [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[(2R)-2-methyl-3-(3- oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (6) (160 mg, 79.63 μmol, 30.79% yield, 40.03% purity, hydrochloric acid) as a light yellow solid. LCMS (ES+): m/z 768.52 [M+H]⁺; Retention time (min): 1.57. Step-5: To a stirred solution of [5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[(2R)- 2-methyl-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone (6) (160 mg, 198.92 μmol, hydrochloric acid) in N,N-dimethylformamide (2 mL) was added DIPEA (128.55 mg, 994.62 μmol, 173.24 μL) and 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1- piperidyl]acetic acid (C-21) (73.11 mg, 159.14 μmol, trifluoroacetic acid) at 0 °C, followed by addition of HATU (113.46 mg, 298.39 μmol). The reaction mixture was stirred at 25 °C for 1an hour. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with ice-cold water (5 mL) to get precipitated solid, which was filtered to get crude product. The crude was purified by prep-HPLC to afford product 3-[4-[1-[2-[4-[5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[(2R)-2-methyl-3-(3-oxa-8-azabicyclo[3.2.1]octan-8- yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 206) (8.8 mg, 6.89 μmol, 3.46% yield, 85.71% purity, no salt) as a light yellow solid. Column/dimensions: X-BRIDGE C18, 5 μm (250mmX19mm); Mobile phase A: 10 mM Ammonium acetate in water; Mobile phase B: 100% acetonitrile Gradient (T%B): 0/10,2/10,16/90; Flow rate: 18mL/min; Solubility: WATER+ACN+THF; LCMS (ES+): m/z 1095.73 [M+H]⁺; Retention time (min): 5.87. ¹H NMR (400 MHz, DMSO- d6): δ 10.75 (s, 1H), 9.91 (s, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 8.8, 6.0 Hz, 1H), 7.38–7.29 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.97–6.91 (m, 2H), 6.67 (s, 1H), 6.59 (d, J = 8.4 Hz, 2H), 5.63 (d, J = 7.6 Hz, 1H), 5.34–5.14 (m, 2H), 4.56–4.48 (m, 3H), 4.42–4.18 (m, 4H), 4.06–3.92 (m, 2H), 3.67–3.53 (m, 4H), 3.51–3.44 (m, 4H), 3.39–3.34 (m, 2H), 3.16 (bs, 2H), 3.04–2.85 (m, 4H), 2.75–2.65 (m, 2H), 2.41–2.36 (m, 2H), 2.27–2.02 (m, 11H), 1.88–1.78 (m, 3H), 1.71–1.51 (m, 4H), 1.00 (d, J = 6.4 Hz, 3H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 182: Synthesis of 3-[4-[1-[2-[4-[5-[2-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-7-(3-morpholinopropoxy)pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4- piperidyl]anilino]piperidine-2,6-dione (Compound 208): O O N N N N N N Cbz N N Cbz HO N 1 O N N NaH, THF, 0°C to RT, 3h N N N N Step-1 Cl N O N Cl N Cl F O F 2 A^-8

Step-1: A solution of 3-morpholinopropan-1-ol 1 (109.00 mg, 750.70 μmol) in tetrahydrofuran (6 mL) was stirred and cooled to 0 °C, NaH ^60% dispersion in oil)^(30.03 mg, 1250 μmol)was then added under argon atmosphere and stirred for 5 minutes. Benzyl 4-[5-(2,7-dichloro-8- fluoro-pyrido[4,3-d]pyrimidin-4-yl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazine-1-carboxylate A-8 (300 mg, 500.46 μmol) was added and allowed to stir at room temperature for 2 hours. The reaction mixture was diluted with ice-cold water (20 mL) and extracted with 10% methanol in dichloromethane (2 x 50 mL). The combined organic layer was washed with saturated brine solution (10 mL), dried over with anhydrous Na2SO4,filtered, and concentrated under reduced pressure to afford benzyl 4-[5-[2-chloro-8-fluoro-7-(3- morpholinopropoxy)pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate 2 (220 mg, 48% yield) as brown gummy. LCMS (ESI): m/z 708.67 [M+H]⁺. Step-2: To a solution of benzyl 4-[5-[2-chloro-8-fluoro-7-(3-morpholinopropoxy)pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1- carboxylate 2 (220 mg, 310.66 μmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 3 (111.91 mg, 310.66 μmol) in mixture of water (0.8 mL) and tetrahydrofuran (4 mL) was added K3PO4 (131.88 mg, 621.31 μmol). The reaction mixture was degassed with argon gas for 10 minutes, then catacxium-Pd-G₃ (22.62 mg, 31.07 μmol) was added, and the resulting reaction mixture was stirred at 100 °C for an hour in a microwave. The reaction mixture was concentrated under reduced pressure to get the crude which was purified by column chromatography using silica gel (100-200 mesh), eluted at 5-6% of methanol in dichloromethane to afford benzyl 4-[5-[2-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-7-(3-morpholinopropoxy)pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate 4 (190 mg, 47% yield) as brown gummy. LCMS (ESI): m/z 907.08 [M+H]⁺. Step-3: To a solution of benzyl 4-[5-[2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-7-(3-morpholinopropoxy)pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate 4 (190 mg, 209.72 μmol) in a mixture of methanol (2 mL) and ethyl acetate (2 mL) was added 10% palladium on carbon (190.00 mg, 1790 μmol). The resulting reaction mixture was stirred at room temperature for 4 hours under hydrogen bladder pressure (1 atm). The reaction mixture was filtered, washed and concentrated under reduced pressure to afford [5-[2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-7-(3-morpholinopropoxy)pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone 5 (140 mg, 62% yield, hydrochloric acid salt) as pale yellow thick liquid. LCMS (ESI): m/z 772.79 [M+H]⁺. Step-4: To a solution of [5-[2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-7- (3-morpholinopropoxy)pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone 5 (140 mg, 181.38 μmol) in dichloromethane (6 mL) was added 4M HCl in 1,4-dioxane (0.2 mL, 181.38 μmol) at 0 °C and stirred for 15 minutes. The reaction mixture was concentrated under vacuum to get the crude product, which was triturated with diethyl ether (5 mL) to afford [5-[2-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-7-(3-morpholinopropoxy)pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone 6 (130 mg, 47% yield, hydrochloric acid salt) as a light yellow solid. LCMS (ESI): m/z 728.70 [M+H]⁺. Step-5: To a stirred solution of [5-[2-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-7-(3- morpholinopropoxy)pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone 6 (100 mg, 130.85 μmol, hydrochloric acid salt) in N,N-dimethylformamide (2 mL) was added DIPEA (0.13 mL, 654.23 μmol) and 2-[4-[4-[(2,6- dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetic acid C-21 (60.11 mg, 130.85 μmol, trifluoroacetic acid salt) at 0 °C followed by addition of HATU (74.63 mg, 196.27 μmol). The resulting reaction mixture was stirred at room temperature for an hour. The reaction mixture was concentrated under reduced pressure to get crude which was purified by prep-HPLC to afford product 3-[4-[1-[2-[4-[5-[2-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-7-(3- morpholinopropoxy)pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]anilino]piperidine-2,6- dione Compound 208 (8 mg, 5% yield) as an off-white solid. LCMS (ES+): m/z 1055.89 [M+H]⁺. Preparative HPLC method: Column/dimensions: KINETEX C18 (21*250, 5μm) Mobile phase A: 0.05% FA in water, Mobile phase B: acetonitrile, Gradient (Time/%B): 0/20, 3/20, 9/40, 10/40, 10.01/95, Flow rate: 17 mL/min, Solubility: Acetonitrile+ THF.¹H NMR (400 MHz, DMSO-d6): δ ( ) (b ) ( ) 7.74 (q, J = 9.2, 6.4 Hz, 1H), 7.37–7.32 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 6.4 Hz, 2H), 6.67 (bs, 1H), 6.59 (d, J = 8.0 Hz, 2H), 5.63 (d, J = 7.6 Hz, 1H), 5.32–5.16 (m, 2H), 4.53 (d, J = 5.6 Hz, 2H), 4.29 (t, J = 6.4 Hz, 2H), 4.38–4.22 (m, 3H), 4.03–3.88 (m, 2H), 3.64–3.46 (m, 12H), 3.16 (bs, 2H), 2.93–2.85 (m, 2H), 2.76–2.56 (m, 2H), 2.43–2.27 (m, 8H), 2.12–2.04 (m, 4H), 1.92–1.78 (m, 3H), 1.69–1.48 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 183: Synthesis of 3-[4-[1-[2-[4-[5-[2-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-7-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]- 4-piperidyl]anilino]piperidine-2,6-dione (Compound 209):

Step-1: A solution of 3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)propan-1-ol 1 (171.40 mg, 1.00 mmol) in tetrahydrofuran (8 mL) was stirred and cooled to 0 ιC, then sodium hydride ( 60% dispersion in mineral oil) (40.03 mg, 1.67 mmol) was added under argon atmosphere, and stirred for 10 minutes. Benzyl 4-[5-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate (A-8) (400 mg, 0.667 mmol) was added and the reaction mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to get crude, which was purified by column chromatography using silica gel (100-200 mesh), eluted at 2% methanol in dichloromethane to afford benzyl 4-[5-[7-chloro-8-fluoro-2-[3-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate 2 (210 mg, 30% yield) as brown solid. LCMS (ESI): m/z 734.65 [M+H]⁺. Step-2: To a solution of benzyl 4-[5-[7-chloro-8-fluoro-2-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8- yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]piperazine-1-carboxylate 2 (210 mg, 286.02 μmol) and 2-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 3 (154.55 mg, 429.03 μmol) in mixture of water (0.4 mL) and tetrahydrofuran (3.2 mL) was added potassium phosphate tribasic (121.42 mg, 572.04 μmol) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes then catacxium-Pd-G3 (20.83 mg, 28.60 μmol) was added, the resulting reaction mixture was stirred at 100 °C for 2 hours in a microwave. The reaction mixture was filtered, washed and the filtrate was concentrated under reduced pressure to obtain crude which was purified by silica gel column chromatography by eluting at 5-6% methanol in dichloromethane to afford benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)- 1-naphthyl]-8-fluoro-2-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1- carboxylate 4 (220 mg, 53% yield) as yellow solid. LCMS (ESI): m/z 932.58 [M+H]⁺. Step-3: To a solution of benzyl 4-[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazine-1-carboxylate 4 (220 mg, 236.05 μmol) in a mixture of methanol (2 mL) and ethyl acetate (2 mL) was added 10% palladium on carbon (220 mg, 207 μmol). The resulting reaction mixture was stirred at room temperature for 5 hours under hydrogen bladder pressure (1 atm). The reaction mixture was filtered, washed and concentrated under reduced pressure to afford [5-[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-2-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8- yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]- piperazin-1-yl-methanone 5 (160 mg, 52% yield) as a pale green solid. LCMS (ESI): m/z 798.62 [M+H]⁺. Step-4: To a solution of [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone 5 (160 mg, 200.53 μmol) in dichloromethane (2 mL) was added 4M HCl solution in 1,4-dioxane (0.6 mL, 200.53 μmol) at 0 °C and stirred for 15 minutes. The reaction mixture was concentrated under vacuum to get the crude product which was triturated with diethyl ether (5 mL) to afford [5-[7-(8-ethyl- 7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8- yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]- piperazin-1-yl-methanone 6 (140 mg, 119.43 μmol, 59% yield, hydrochloric acid salt) as light yellow solid. LCMS (ESI): m/z 754.70 [M+H]⁺. Step-5: To a stirred solution of [5-[2-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-7-[3-(3- oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-piperazin-1-yl-methanone 6 (120 mg, 151.84 μmol, hydrochloric acid salt) in N,N-dimethylformamide (2 mL) was added DIPEA (98.12 mg, 759.21 μmol) and 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetic acid C-21 (48.83 mg, 106.29 μmol, trifluoroacetic acid salt) at 0 °C followed by addition of HATU (86.60 mg, 227.76 μmol). The resulting reaction mixture was stirred at room temperature for an hour. The reaction mixture was concentrated under reduced pressure to get crude which was purified by prep-HPLC to afford 3-[4-[1-[2-[4-[5-[2-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 7-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]piperazin-1-yl]-2-oxo-ethyl]-4- piperidyl]anilino]piperidine-2,6-dione Compound 209 (9 mg, 5% yield) as an off-white solid. LCMS (ESI): m/z 1079.84 [M-H]-. Preparative HPLC method: Column/dimension: X-SELECT C18, 5 μm (100 mm x 19 mm) Mobile Phase A: 0.1% FA in water Mobile Phase B: acetonitrile Gradient (T%B): 0/10, 2/15, 7.50/48.70, 7.60/98, 11/98,11.10/10,13.50 Flow Rate: 18 mL/min Sample Diluent: Acetonitrile+ water+ THF. ¹H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 9.92 (bs, 1H), 9.19 (s, 1H), 7.78–7.74 (q, J = 9.2, 6.0 Hz, 1H), 7.38–7.30 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.97–6.91 (m, 2H), 6.67 (bs, 1H), 6.59 (d, J = 8.4 Hz, 2H), 5.63 (d, J = 7.6 Hz, 1H), 5.34–5.16 (m, 2H), 4.53–4.44 (m, 4H), 4.39–4.21 (m, 3H), 4.03–3.88 (m, 2H), 3.64–3.37 (m, 10H), 3.16 (bs, 2H), 3.04 (bs, 2H), 2.92–2.85 (m, 2H), 2.75–2.56 (m, 2H), 2.41–2.27 (m, 6H), 2.13–2.02 (m, 4H), 1.90–1.78 (m, 5H), 1.71–1.49 (m, 6H), 0.71 (t, J = 7.2 Hz, 3H). Synthesis 184: Synthesis of 3-[6-[1-[[1-[5-[7-(7,8-difluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-4-piperidyl]-1- methyl-indazol-3-yl]piperidine-2,6-dione (Compound 281) Step-1: To a stirred solution of ethyl 5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo- [1,5-a][1,4]diazepine 2 carboxylate 1 (200 mg 36497 μmol) and 2-[7,8-difluoro-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (255.60 mg, 729.95 μmol) in the mixture of water (0.5 mL) and tetrahydrofuran (1.5 mL) was added K₃PO₄ (232.42 mg, 1.09 mmol) and was degassed with nitrogen for 15 minutes, followed by addition of cataCXium® A Pd G3 (53.16 mg, 72.99 μmol) and heated to stir at 100 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain crude which was purified by column chromatography (silica 100-200 mesh) using 60-70% ethyl acetate in petroleum ether as an eluent to afford ethyl 5-[7-[7,8-difluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 9 (250 mg, 86% yield) as brown gummy. LCMS (ESI): m/z 736.71 [M+H]⁺ _. Step-2: To a solution of ethyl 5-[7-[7,8-difluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 3 (250 mg, 339.80 μmol) in water (1 mL) and methanol (0.5 mL) was added LiOH (40 mg) at 0 °C and then stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to get the crude compound, which was purified by reverse phase column chromatography using 0.1% ammonium bicarbonate in water and acetonitrile to afforded the product 5-[7-[7,8-difluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 4 (130 mg,45% yield) as an off white solid. LCMS (ESI): m/z 708.82 [M+H]⁺. Step-3: To a stirred solution of 5-[7-[7,8-difluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 4 (130 mg, 183.70 μmol) in dichloromethane (1 mL) was added 4M HCl in 1,4-dioxane (0.1 mL) at 0 °C and then at room temperature for an hour. The reaction mixture was concentrated under reduced pressure to get crude product which was triturated with diethyl ether to afford 5-[7-(7,8-difluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxylic acid 5 (110 mg, 58% yield, hydrochloric acid salt) as off-white solid. LCMS (ESI): m/z 382.61 [M+H]⁺ Step-4: To a stirred solution of 5-[7-(7,8-difluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 5 (70 mg, 99.99 μmol, hydrochloric acid salt) and 3-[1-methyl-6-[1-(4-piperidylmethyl)-4-piperidyl]indazol-3-yl]piperidine-2,6- dione 6 (36.80 mg, 79.99 μmol, hydrochloric acid salt) in N,N-dimethylformamide (1 mL) was added DIPEA (38.77 mg, 299.97 μmol) followed by addition of HATU (57.03 mg, 149.98 μmol) and stirred at room temperature for 12 hours. The reaction mixture was lyophilized to get crude product which was purified by Prep-HPLC to afford 3-[6-[1-[[1-[5-[7-(7,8-difluoro-3-hydroxy- 1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-4-piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 281 (8 mg,7% yield) as an off-white solid. LCMS (ESI): m/z 1069.18 [M+H]⁺. Prep- HPLC method: Column/dimensions: XSELECT C18(10*250, 5μm) Mobile phase A: 0.1% ammonium acetate in water, Mobile phase B: acetonitrile, Gradient (Time/%B): 0/30, 3/30,7/40 12/40, Flow rate: 17 mL/min, solubility: Acetonitrile+ THF.¹H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 10.33 (bs, 1H), 9.19 (s, 1H), 7.76–7.72 (m, 1H), 7.60–7.53 (m, 2H), 7.43 (s, 1H), 7.39 (s, 1H), 7.24 (d, J = 2 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.59 (s, 1H), 5.35–5.19 (m, 3H), 4.61–4.48 (m, 4H), 4.32–4.30 (m, 3H), 4.14–4.02 (m, 2H), 3.96 (s, 3H), 3.07 (m, 3H), 2.93 (m, 2H), 2.82 (m, 1H), 2.71 (m, 1H), 2.68 (m, 2H), 2.61–2.50 (m, 4H), 2.32 (m, 2H), 2.20–2.10 (m, 4H), 2.05–1.93 (m, 3H), 1.90 (m, 3H), 1.83–1.75 (m, 8H), 1.03 (m, 2H). Synthesis 185: Synthesis of 3-[6-[1-[[1-[5-[6-chloro-7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]quinazolin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-

4-piperidyl]methyl]-4-iperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 298): To a stirred solution 5-[6-chloro-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-11 (70 mg, 94.14 μmol, HCl salt) and 3-[1-methyl-6-[1-(4-piperidylmethyl)-4-piperidyl]indazol-3-yl]piperidine-2,6-dione 12 (34.64 mg, 75.31 μmol, HCl salt) in N,N-dimethylformamide (1 mL) were added diisopropylethylamine (250 mg, 1.93 mmol) and HATU (54.91 mg, 144.40 μmol) at 0 °C. The resulting mixture was allowed to stir at room temperature for 16 hours. The crude mixture was the lyophilized to get crude which was purified by prep HPLC method to afford 3-[6-[1-[[1-[5- [6-chloro-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]methyl]-4-piperidyl]-1- methyl-indazol-3-yl]piperidine-2,6-dione Compound 298 (6 mg, 4 % yield) as an off-white solid. LCMS (ESI): m/z 1112.58 [M+H]⁺. Preparative HPLC method: Column/dimensions: X- Select C18 (10*250mm) 5μm Mobile phase A: 10 mM ABC in water, Mobile phase B: 100% Acetonitrile, Gradient (Time/%B) :0/40, 3/40, 7/65, 13/65, 14/100, Flow Rate: 7 mL/min. Solubility: Acetonitrile+ THF+ water. ¹H NMR (400 MHz, DMSO-d6): δ 10.87 (bs, 1H), 9.98 (bs, 1H), 8.75 (s, 1H), 7.84–7.79 (m, 1 H), 7.60–7.58 (m, 1H), 7.45–7.43 (m, 1H), 7.36–7.31 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 6.87 (bs, 1 H), 5.40–4.98 (m, 3H), 4.59–4.20 (m, 10H), 3.96 (bs, 3H), 3.12–2.82 (m, 8H), 2.30–2.04 (m, 10 H), 1.86–1.63 (m, 10 H), 1.30–0.98 (m, 7H), 0.90– 0.81 (m, 1H), 0.72 (t, d = 7.2 Hz, 3H). Synthesis 186: Synthesis of 3-(6-(1-((1-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2- carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione (Compound 299):

To a stirred solution 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-6,8-difluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-12 (70 mg, 96.27 μmol, HCl salt) and 3-[1-methyl-6-[1-(4-piperidylmethyl)-4-piperidyl]indazol-3-yl]piperidine-2,6-dione 10 (35.43 mg, 77.01 μmol, HCl salt) in N,N-dimethylformamide (1 mL) were added diisopropylethylamine (248.83 mg, 1.93 mmol) and HATU (54.91 mg, 144.40 μmol) at 0 °C. The resulting reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was lyophilized to get crude which was purified by preparative HPLC method to afford 3-[6-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-6,8-difluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]methyl]-4-piperidyl]-1- methyl-indazol-3-yl]piperidine-2,6-dione Compound 299 (16 mg, 14 % yield) as an off-white solid. LCMS (ESI): m/z 1096.91 [M+H]⁺. Preparative HPLC method: Column/dimensions: X- Select C18 (10*250mm) 5μm Mobile phase A: 10 mM ABC in water, Mobile phase B: 100% acetonitrile, Gradient (Time/%B):0/40, 3/40, 7/65, 13/65, 14/100, Flow Rate: 7 mL/min. Solubility: Acetonitrile+ THF+ water. ¹H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 10.01 (bs, 1H), 7.79-7.75 (m, 2H), 7.60-7.58 (d, J = 8 Hz, 1H),7.43 (s, 1H), 7.38-7.34 (m, 3H), 6.52 (s, 1H), 5.13-5.06 (m, 5H), 4.51-4.48 (m, 4H), 4.42-4.32 (m, 1H), 4.31-4.11 (m, 6H), 3.96 (s, 3H), 3.12-2.90 (m, 8H), 2.85-2.80 (m, 1H), 2.71-2.60 (m, 6H), 2.40-2.31 (m, 4H), 2.22-2.12 (m, 1H),1.85-1.61 (m, 10H), 1.23-1.02 (m, 2H), 0.75-0.72 (d, J = 6 Hz, 3H) ppm. Synthesis 187: Synthesis of 3-[4-[1-[2-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]ethyl]-4-piperidyl]-3-fluoro-anilino]piperidine-2,6-dione (Compound 324) To a stirred solution of 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 1 (70 mg, 98.57 μmol, hydrochloric acid salt) and 3-[3-fluoro-4-[1-[2-(4-piperidyl)ethyl]-4- piperidyl]anilino]piperidine-2,6-dione 2 (35.72 mg, 78.86 μmol, hydrochloric acid salt ) in N,N- dimethylformamide (1.5 mL) was added DIPEA (0.05 mL, 295.71 μmol) and HATU (56.22 mg, 147.86 μmol) at 0 °C. The resulting reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was lyophilized to get crude compound which was purified by prep-HPLC to afford 3-[4-[1-[2-[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]ethyl]-4- piperidyl]-3-fluoro-anilino]piperidine-2,6-dione Compound 324 (25 mg, 18% yield, trifluoroacetic acid salt) as pale green solid. LCMS (ESI): m/z 1072.85 [M+H]⁺. Prep-HPLC method: [Column: X-SELECT C18, 5 μm (250 mm x 19 mm), Mobile Phase A: 0.1% TFA in water, B: acetonitrile Gradient (T%B):0/10, 2/25, 15/70, 15.10/98, 17.50/98,17.60/10, 20/10, Flow Rate: 18 mL/min Sample Diluent: Acetonitrile+ water+ THF]. ¹H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1H), 10.69 (bs, 1H), 9.95 (s, 1H), 9.27 (s, 1H), 9.11 (bs, 1H), 7.79–7.76 (m, 1H), 7.38–7.34 (m, 2H), 7.00 (d, J = 2.4 Hz, 1H), 9.96–9.91 (m, 1H), 6.67 (s, 1H), 6.49– 6.45 (m, 2H), 6.12 (bs, 1H), 5.30–5.00 (m, 2H), 5.38–5.19 (m, 2H), 4.71–4.30 (m, 9H), 3.91– 3.71 (m, 4H), 3.56 (m, 2H), 3.25 (m, 1H), 2.11–2.99 (m, 5H), 2.60 (m, 1H), 2.41–2.31 (m, 4H), 2.62–2.01 (m, 5H), 1.92–1.80 (m, 6H), 1.78–1.51 (m, 5H), 1.11 (m, 2H), 0.70 (t, J = 7.2 Hz, 3H) ppm. Synthesis 188: Synthesis of 3-[6-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-3-fluoro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 325)

To a stirred solution 5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-3-fluoro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid A-9 (35 mg, 0.048 mmol, hydrochloric acid salt) and 3-[1-methyl-6-[1-(4-piperidylmethyl)-4- piperidyl]indazol-3-yl]piperidine-2,6-dione 8 (26 mg, 0.057 mmol, hydrochloric acid salt) in N,N-dimethylformamide (1 mL) were added DIPEA (0.025 mL, 0.144 mmol) and HATU (27 mg, 0.072 mmol) at 0 °C . The resulting reaction mixture was allowed to stir at room temperature for 16 hours, the reaction mixture was lyophilized to get crude product which was purified by prep HPLC method to afford 3-[6-[1-[[1-[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-3-fluoro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 325 (13 mg, 20 % yield) as an off-white solid, LCMS[ESI]: m/z 1097.53[M+H]⁺. Prep HPLC method: [Column/dimensions: X-Select C18 (10 * 250 mm) 5μm Mobile phase A: 10 mM ABC in water+0.1 % ammonia, Mobile phase B: 100% acetonitrile, Gradient (Time/%B):0/30, 2/30, 7/55, 14/55, 14.10/100, 16.00/100, 16.10/30, Flow Rate: 7 mL/min. Solubility: Acetonitrile+THF +Water].¹H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 9.92 (s, 1H), 9.17 (s, 1H), 7.76 (q, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.43(s, 1H) ,7.37-7.32 (m, 2H), 7.03-7.00 (m, 2H), 5.40-5.10 (m, 3H), 4.45-4.30 (m, 6H), 4.14-4.09 (m, 3H), 3.96 (bs, 3H), 3.08-3.06 (m, 3H), 3.00-2.95 (m, 3H), 2.64-2.61 (m, 2H), 2.18-1.97 (m, 10 H), 1.90-1.74 (m, 10 H), 1.23-1.17 (m, 5H), 1.07-1.03 (m, 2H), 0.90-0.81 (m, 1H), 0.72 (t, J = 7.2 Hz, 3H). Synthesis 189: Synthesis of 3-[6-[1-[[1-[3-chloro-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-

2-carbonyl]-4-piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 326) O O NH N OH O N N Cl HN N F N N Et 1 N N HATU, DIPEA, DMF,RT, 16h N O N F OH F A-10 To a stirred solution of 3-chloro-5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 10 (80 mg, 107.44 μmol, hydrochloric acid salt) and 3-[1-methyl-6-[1-(4-piperidylmethyl)-4-piperidyl]indazol-3- yl]piperidine-2,6-dione 11 (39.54 mg, 85.95 μmol, hydrochloric acid salt) in N,N- dimethylformamide (1.5 mL) at 0 °C was added DIPEA (41.66 mg, 322.33 μmol) followed by addition of HATU (61.28 mg, 161.16 μmol). The resulting reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was lyophilized to get crude which was purified by prep-HPLC method to afford 3-[6-[1-[[1-[3-chloro-5-[7-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbonyl]-4-piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 326 (7 mg, 6% yield) as an off-white solid, LCMS (ESI): m/z 1113.85 [M+H]⁺. Prep-HPLC method: Column/dimensions: XSELECT C18 (19*250, 5μm) Mobile phase A: 5 mM ammonium bicarbonate in water, Mobile phase B: acetonitrile, Gradient (Time/%B): 050, 2/50, 12/5012.1/100, Flow rate: 17 mL/min, Solubility: Acetonitrile+THF. ¹H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 1H),7.78–7.74 (m, 1H),7.59 (d, J= 8.4 Hz, 1H), 7.42 (s, 1H), 7.37–7.32 (m, 2H), 7.03–7.0 (m, 2H), 5.50–5.02 (m, 3H), 4.59–4.42 (m, 3H), 4.49–4.25 (m, 3H), 4.21– 4.06 (m, 2H), 3.96 (s, 3H), 3.82–3.75 (m, 1H), 3.10–2.95 (m, 8H), 2.89–2.71 (m, 3H), 2.68–2.58 (m, 3H), 2.40 (m, 2H), 2.22–2.18 (m, 4H), 2.05–2.0 (m, 4H), 1.95–1.80 (m, 5H),1.78–1.65 (m, 5H), 1.50–1.11 (m, 4H) 0.71 (t, J = 7.2 Hz, 3H). Synthesis 190: Synthesis of 3-[4-[1-[2-[1-[5-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carbonyl]-4-piperidyl]ethyl]-4-piperidyl]anilino]piperidine-2,6-dione (Compound 327)

Step-1: To a stirred solution of ethyl 5-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 1 (300 mg, 547.46 μmol) and 2-[2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- naphthyl]ethynyl-triisopropyl-silane 2 (561.19 mg, 1.09 mmol) in a mixture of tetrahydrofuran (2 mL) and water (0.5 mL) was added K3PO4 (348.63 mg, 1.64 mmol). The reaction mixture was degassed with argon for 5 minutes. Catacxium Pd G3 (79.74 mg, 109.49 μmol) was added, and reaction mixture was heated to stir at 100 °C for 2 hours in a microwave. The reaction mixture was concentrated under reduced pressure to afford crude compound which was purified by flash column chromatography (100-200 silica) using 3-5% methanol in dichloromethane as an eluent to afford ethyl 5-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1- naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxylate 3 (330 mg, 59 % yield) as a brown solid. LCMS (ESI): m/z 898.86 [M+H]⁺. Step-2: To stirred a solution of ethyl 5-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropyl- silylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylate 3 (300 mg, 334.04 μmol) in a mixture of methanol (1 mL), tetrahydrofuran (1 mL) and water (0.5 mL) at 0 °C was added LiOH. The reaction mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to get crude compound which was purified by reverse phase column chromatography to afford 5-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1- naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxylic acid 4 (120 mg, 24 % yield) as a brown solid. LCMS (ESI): m/z 870.84 [M+H]⁺. Step-3: To the stirred solution of 5-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 4 (100 mg, 114.94 μmol) in N,N- dimethylformamide (1 mL) was added cesium fluoride (87.30 mg, 574.68 μmol) at 0 °C. The resulting reaction mixture was allowed to stir at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with 10% methanol in dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 5-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 5 (100 mg, 63% yield) as yellow gummy. LCMS (ESI): m/z 714.73 [M+H]⁺. Step-4: To the stirred solution of 5-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 5 (100 mg, 140.11 μmol) in dichloromethane (1 mL) was added 4 M HCl in 1,4-dioxane (0.2 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for an hour. The reaction mixture was concentrated under reduced pressure to get crude product which was triturated with diethyl ether to afford 5-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahyd li i l h id d i idi -4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 6 (80 mg, 64 % yield, hydrochloric acid salt) as a grey solid. LCMS (ESI): m/z 670.09 [M+H]⁺. Step-5: To a stirred solution of 5-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid 6 (80 mg, 113.30 μmol, hydrochloric acid salt) and 3-[4-[1-[2-(4-piperidyl)ethyl]-4-piperidyl]anilino]piperidine-2,6- dione 7 (39.43 mg, 90.64 μmol, hydrochloric acid salt) in N,N-dimethylformamide (1.5 mL) at 0 °C was added DIPEA (43.93 mg, 339.89 μmol) followed by addition HATU (64.62 mg, 169.94 μmol). The resulting reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was lyophilized to get crude which was purified by Prep-HPLC to afford 3-[4- [1-[2-[1-[5-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbonyl]-4-piperidyl]ethyl]-4- piperidyl]anilino]piperidine-2,6-dione Compound 327 (12 mg, 9.58% yield) as an off-white solid. LCMS (ESI): m/z 1050.77 [M+H]⁺. Prep-HPLC method: Column/dimensions: X BRIDGE C8 (10*250mm) 5μm, Mobile phase A: 10 mM ammonium acetate in water, Mobile phase B: 100% acetonitrile, Gradient (Time/%B): 0/15, 2/15, 9.6/70, 9.61/100, Flow rate: 7 mL/min, Solubility: Acetonitrile+ water+ THF. ¹H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 10.20 (bs, 1H), 9.12 (s, 1H), 7.99–7.95 (m, 1H), 7.48–7.44 (m, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.60–6.58 (m, 3H), 5.63 (d, J = 7.2 Hz, 1H), 5.20–5.17 (m, 3H), 4.71–4.57 (m, 1H), 4.55–4.40 (m, 3H), 4.38–4.21 (m, 3H), 4.19–3.98 (m, 3H), 3.20– 3.0 (m, 4H), 2.95–2.90 (m, 2H), 2.87–2.89 (m, 1H), 2.73–2.68 (m, 1H), 2.60–2.50 (m, 3H), 2.45– 2.40 (m, 3H), 2.32 (m, 2H), 2.09–1.91 (m, 3H), 1.85 (m, 2H), 1.70–1.68 (m, 5H), 1.63–1.50 (m, 4H), 1.42–1.30 (m, 2H), 1.28 (m, 1H), 1.13–0.95 (m, 2H) ppm. Synthesis 191: Synthesis of 3-[6-[1-[[1-[[5-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]methyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 328)

Step-1: A solution of ethyl 5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 1 (200 mg, 268.17 μmol) in dichloromethane (5 mL) was cooled to -78 °C, then DIBAL-H (1M in toluene, 0.54 mL, 536.35 μmol) was added and the reaction mixture was allowed to stir at 0 °C for 4 hours. The reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to get crude, which was purified by silica gel (100-200 mesh) column chromatography eluted at 0-2% methanol in dichloromethane to afford [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2- yl]methanol 2 (120 mg, 59% yield) as an off-white solid. LCMS (ESI): m/z 705.13 [M+H]⁺. Step-2: A stirred solution of [5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]methanol 2 (200 mg, 284.19 μmol) in a mixture of dichloromethane (1 mL) and acetonitrile (1 mL) was cooled to 0 °C. Dess–Martin periodinane (241.07 mg, 568.38 μmol) was then added portion wise over a period of 5 minutes. The resulting reaction mixture was heated to 80 °C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with 10% methanol in dichloromethane. The organic layer was dried over with anhydrous sodium sulphate, filtered and evaporated under reduced pressure to afford 5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carbaldehyde 3 (140 mg, 47 % yield) as a yellow solid. LCMS (ESI): m/z 703.02 [M+H]⁺. Step-3: To a stirred solution of 3-[1-methyl-6-[1-(4-piperidylmethyl)-4-piperidyl]indazol-3- yl]piperidine-2,6-dione 4 (98.33 mg, 213.76 μmol, hydrochloric acid salt) in dimethyl sulfoxide (1 mL) was added NaOAc (70.14 mg, 855.02 μmol), acetic acid (0.12 mL, 2.1 mmol) and 5-[7- [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carbaldehyde 3 (140 mg, 0.21 mmol). The reaction mixture was allowed to stir at room temperature for 3 hours. MP-Cyano borohydride (26.93 mg, 427.51 μmol) was added, and the reaction mixture was heated to stir at 70 °C for 16 hours. The reaction mixture was lyophilized and filtered to get crude, which was purified by Prep-HPLC method to afford 3-[6-[1-[[1-[[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]methyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione 5 (20 mg, 8 % yield) as an off-white solid. LCMS (ESI): m/z 1109.05 [M+H]⁺. Prep-HPLC method: Column/dimensions: X-SELECT C18 (10 x 250) 5μ, Mobile phase A: 10 mM ABC +0.1% ammonia solution in water, Mobile phase B: 100% acetonitrile + spiked with 0.1% ammonia solution, Gradient (Time/%B): 0/30, 3/30, 7/70, 15/70, Flow rate: 17 mL/min. Solubility: Water+ THF+ acetonitrile. Step-4: To a stirred solution of 3-[6-[1-[[1-[[5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2- yl]methyl]-4-piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione 5 (20 mg, 18.03 μmol) was added 4M HCl in 1,4-dioxane (0.05 mL, 18.03 μmol) at 0 °C and stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure to get crude, which was triturated with diethyl ether to afford 3-[6-[1-[[1-[[5-[7-(8-ethyl-7-fluoro-3-hydroxy- 1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]- pyrido[4,3-d]pyrimidin-4-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]methyl]-4- piperidyl]methyl]-4-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione Compound 328 (16 mg, 74% yield, hyd hl i id l) ll lid ( ) m/z 1065.79 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6): δ 11.19–11.04 (bs, 1H), 10.89 (s, 1H), 10.87–10.75 (bs, 1H), 10.37–10.24 (bs, 1H), 10.09–9.96 (bs, 1H), 9.24 (s, 1H), 7.80–7.74 (m, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.41–7.33 (m, 3H), 7.18–6.99 (m, 3H), 6.77 (s, 1H), 5.71–5.55 (m, 1H), 5.40–5.19 (m, 2H), 4.65 (bs, 2H), 4.52 (bs, 2H), 4.41–4.29 (m, 3H), 4.20 (bs, 2H), 4.03–3.76 (m, 6H), 3.41–3.18 (m, 7H), 3.09–2.87 (m, 7H), 2.43–2.26 (m, 4H), 2.22–1.91 (m, 12H), 1.67–1.55 (m, 2H), 0.72 (t, J = 7.2 Hz, 3H). Table 3A Non-limiting Examples of Compounds of the Present Invention Compound 1 Compound 2 Compound 3

Compound 4 Compound 5 Compound 6

Compound 7 Compound 8 Compound 9

Compound 10 Compound 11 Compound 12 Compound 13

Compound 14 Compound 19

Compound 20

Compound 21

Compound 22 Compound 23

Compound 24 H HO ^* _* O N N O F N O H N Et O N N N N N O N O F OH F * Relative trans stereochemistry H HO O N N O F N O H N Et O N N N N N O N O F OH F H HO O N N O F N O H N Et O N N N N N O N O F OH F H HO O N N O F N O H N Et O N N N N N O N O F OH F Compound 25

Compound 27 Compound 28

Compound 29

Compound 30

Compound 31

Compound 32

Compound 34 Compound 35 Compound 36

Compound 37 Compound 38 Compound 39

Compound 40 Compound 41 Compound 42

Compound 43 Compound 44 Compound 45

Compound 46 Compound 47 Compound 48 O O N N 7 N O N N O ^N _N NH O O F HN N N N O N F OH F Compound 49 Compound 54 Compound 55

Compound 57 Compound 58 Compound 59

Compound 60 Compound 61 Compound 62

Compound 63 Compound 64 Compound 65

Compound 66 Compound 67 Compound 68

Compound 69 Compound 70 Compound 71

Compound 72 Compound 73 Compound 96 Compound 129

Compound 130 O N O N N N N O F N O _H F N Et N N N F N O HO N F Compound 192 Compound 193 Compound 224

Compound 225 Compound 227 Compound 298 O HN O O N N N N N N F Cl N Et N N F O N HO F

Compound 299 Compound 300 Compound 301

Compound 302 Compound 305 Compound 311 Compound 317

Compound 325 Compound 326 Compound 328 F N N O N N N NH N HO N F O N N O N N F

Table 3B Additional Non-limiting Examples of Compounds of the Present Invention Compound 15 Compound 16 Compound 17

Compound 18 Compound 33

Compound 50 Compound 51

Compound 52 Compound 53 Compound 56

Compound 74 Compound 75 Compound 76

Compound 77 Compound 78 Compound 79

Compound 80 Compound 81 Compound 82

Compound 83 Compound 84 Compound 85

Compound 86 Compound 87 Compound 88

Compound 89 Compound 90 Compound 91

Compound 92 Compound 93 Compound 94

Compound 95 Compound 97 Compound 98

Compound 99 Compound 100 Compound 101

Compound 102 Compound 103 Compound 104

Compound 105 Compound 106 Compound 107 Compound 108

Compound 109 Compound 110 Compound 111 Compound 112

Compound 113 Compound 114 Compound 115

Compound 116 Compound 117 Compound 118

Compound 119 Compound 120 Compound 121

Compound 122 Compound 123 Compound 124

Compound 125 Compound 126 Compound 127

Compound 128 Compound 131 Compound 132

Compound 133 Compound 134 Compound 135

Compound 136 Compound 137 Compound 138

Compound 139 Compound 140 Compound 141

Compound 142 Compound 143 Compound 144 O N N N N ^H O _N ^O F N N H N N N O N F OH F Compound 145 Compound 146 Compound 147

Compound 148 Compound 149 Compound 150 Compound 151

Compound 152 Compound 153 Compound 154 Compound 155

Compound 156 Compound 157 Compound 158 Compound 159

Compound 160 Compound 161 Compound 162

Compound 163 Compound 164 Compound 165

Compound 166 Compound 167 Compound 168

Compound 169 Compound 170 Compound 171

Compound 172 Compound 173 Compound 174 Compound 175

Compound 176 Compound 177 Compound 178

Compound 179 Compound 180 Compound 181 Compound 182

Compound 183 Compound 184 Compound 185 Compound 186

Compound 187 Compound 188 Compound 189 Compound 190

Compound 191 Compound 194 Compound 195 Compound 196

Compound 197 Compound 198 Compound 199 Compound 200

Compound 201 Compound 202 Compound 203

Compound 204 Compound 205 Compound 206

Compound 207 Compound 208 Compound 209 Compound 210

Compound 211 Compound 212 Compound 213 Compound 214

Compound 215 Compound 216 Compound 217 Compound 218

Compound 219 Compound 220 Compound 221 Compound 222

Compound 223 Compound 226 Compound 228 Compound 229

Compound 230 Compound 231 Compound 232 Compound 233

Compound 234 Compound 235 Compound 236 Compound 237

Compound 238 Compound 239 Compound 240 Compound 241

Compound 242 Compound 243 Compound 244 Compound 245

Compound 246 Compound 247 Compound 248 Compound 249

Compound 250 Compound 251 Compound 252 Compound 253

Compound 254 Compound 255 Compound 256 Compound 257

Compound 258 Compound 259 Compound 260 Compound 261

Compound 262 Compound 263 Compound 264 Compound 265

Compound 266 Compound 267 Compound 268 Compound 269

Compound 270 Compound 271 Compound 272

Compound 273 Compound 274 Compound 275

Compound 276 Compound 277 Compound 278

Compound 279 Compound 280 Compound 281

Compound 282 Compound 283 Compound 284

Compound 285 Compound 286 Compound 287

Compound 288 Compound 289 Compound 290

Compound 291 Compound 292 Compound 293

Compound 294 Compound 295 Compound 296

Compound 297 Compound 303 Compound 304

Compound 306 Compound 307 Compound 308

Compound 309 Compound 310 Compound 312

Compound 313 Compound 314 Compound 315

Compound 316 Compound 318 Compound 322

Compound 324 Compound 327 Compound 329 Example 5: HiBiT KRAS Degradation Assay Phenol red-free Dulbecco’s modified Eagle medium (DMEM), phenol-red free Leibovitz’s L-15 medium, fetal bovine serum (FBS), and 1 M HEPES were purchased from Thermo Fisher Scientific (Waltham, MA, USA). The Nano-Glo® HiBiT Lytic Assay System was purchased from Promega (Madison, WI, USA). Cell culture flasks and 384-well microplates were acquired from VWR (Radnor, PA, USA). The following ready-to-use HiBiT reporter cell lines were acquired from Promega (Madison, WI, USA): HEK293-KRAS-WT (Cat#CS3023186) exclusively expressing HiBiT-KRAS-WT wild-type protein (also referred to here as HEK293.8); HEK293-KRAS-G12D (Cat#CS3023372) exclusively expressing HiBiT- KRAS-G12D mutant protein (also referred to here as HEK293.7); and SW620-KRAS-G12V (Cat#3023152) exclusively expressing HiBiT-KRAS-G12V mutant protein (also referred to here as SW620.2). For each of these cell lines, the HiBiT fusion tag was genetically engineered into the N-terminus of endogenously expressed KRAS via CRISPR. HiBiT-KRAS degradation was evaluated by the quantification of luminescent signals using the Nano-Glo® HiBiT Lytic Assay kit. Test compounds were added to 384-well plates in duplicate using an 11-point half-log dilution series, with the highest dose set to 10 μΜ. The HEK293.8, HEK293.7, or SW620.2 cells in their respective growth medium were then added into the compound-containing 384-well plates. The HEK293-KRAS-WT and HEK293-KRAS- G12D cells were cultured in DMEM-based growth medium supplemented with 10% FBS and 10 mM HEPES; while SW620-KRAS-G12V cells were maintained in L-15 medium supplemented with 10% FBS and 10 mM HEPES. The cellular plating density per well in the 30 μL total assay volume for each cell line is as follows: 10,000 cells for HEK293-KRAS-WT and HEK293-KRAS-G12D cells; and 7,000 cells for SW620-KRAS-G12V cells. Upon cell addition, plates with HEK293.8 or HEK293.7 cells were incubated with compounds at 37 °C with 5% CO2 for 24 hours. As a CO2 and air mixture are detrimental to SW620-KRAS-G12V cells using L-15 medium, this cell line was incubated in a humidified 37 °C incubator without CO_2. Following the 24-hour incubation, Nano-Glo^® HiBiT Lytic Assay reagents were added to the cells per the manufacturer’s instructions. Luminescence was acquired using an EnVision™ Multilabel Reader (PerkinElmer, Santa Clara, CA, USA). Quantification of luminescence responses measured in the presence of compound were normalized to a high signal/no degradation control (untreated cells + lytic detection reagent) and a low signal/full degradation control (untreated cells, no lytic detection reagent). Data were analyzed with a 4-parameter logistic fit to generate sigmoidal dose-response curves. The DC50 is the concentration of compound at which exactly 50% of the total cellular KRAS has been degraded. The Emax, or maximum effect of each compound, represents the amount of residual protein remaining in the cell following compound treatment. The IP, or inflection point of the dose-response curve, is the concentration of compound at which 50% of the observed degradation response is achieved. Tables 4-6 show the activity of selected compounds of this invention in the in vitro KRAS HiBiT degradation assays with SW620-KRAS-G12V, HEK293-KRAS-G12D, and HEK293-KRAS-WT cells, respectively, wherein each compound number corresponds to the compound numbe i f h i h i d ib d h in. The experiment was conducted at least once for each compound identified in Tables 4-6, where if the experiment was conducted multiple times, then the data shown in the table is the average of the two or more experiments. “++++” represents a DC₅₀ or IP value of less than 100 nM or an Emax of less than 10%. “+++” represents a DC50 or IP value of 100 nM–500 nM or an Emax value of 10%–50%. “++” represents a DC₅₀ or IP value of 500 nM–1000 nM or an Emax value of 50%–90%. “+” represents a DC50 or IP value of greater than 1000 nM or an Emax value of more than 90%. N.A. means Emax is greater than or equal to 50%. Table 4. in vitro KRAS HiBiT degradation assays with SW620-KRAS-G12V cells HiBiT- HiBiT- HiBiT- Degradation Degradation Degradation SW620.2 SW620.2 SW620.2 Compound KRAS_G12V KRAS_G12V KRAS_G12V (KI) (KI) (KI) 24 hours 24 hours 24 hours DC50 nM Emax IP nM 1 N.A. ++ + 2 N.A. + + 3 N.A. + + 4 N.A. + + 5 N.A. + + 7 N.A. + + 8 N.A. + + 9 N.A. + + 10 N.A. + + 11 N.A. ++ + 12 N.A. + + 13 N.A. ++ + 14 N.A. + ++++ 15 N.A. + + 16 N.A. + + 19 N.A. + + 20 N.A. + + 21 N.A. + + 22 N.A. + + 23 N.A. ++ + 24 N.A. + + 25 N.A. + + 26 N.A. + + 27 N.A. + + 28 N.A. ++ + 29 N.A. + + 30 N.A. + + 31 N.A. + + 32 N.A. + + 33 N.A. + + 34 N.A. ++ +++ 35 N.A. + + 36 N.A. + + 37 N.A. + + 38 N.A. + + 39 N.A. + + 40 N.A. ++ +++ 41 N.A. ++ +++ 42 N.A. ++ + 43 N.A. ++ +++ 44 N.A. ++ ++ 45 + +++ ++ 46 N.A. ++ ++ 47 N.A. ++ ++ 48 N.A. ++ + 49 N.A. + ++ 50 N.A. + + 51 N.A. + + 52 N.A. + + 53 N.A. ++ + 54 N.A. ++ +++ 55 N.A. ++ +++ 56 N.A. ++ ++ 57 N.A. ++ +++ 58 N.A. + + 59 N.A. ++ +++ 60 N.A. ++ + 61 N.A. + + 62 N.A. + ++ 63 N.A. + ++ 64 N.A. ++ +++ 65 N.A. ++ +++ 66 N.A. ++ +++ 67 N.A. ++ +++ 68 N.A. ++ ++ 69 N.A. ++ +++ 70 N.A. ++ +++ 71 N.A. ++ +++ 72 N.A. + +++ 73 N.A. + +++ 74 N.A. + + 75 N.A. ++ +++ 76 N.A. ++ ++++ 77 ++ +++ +++ 78 N.A. ++ + 79 N.A. + + 80 N.A. + + 81 N.A. ++ + 82 N.A. ++ +++ 83 N.A. ++ +++ 84 N.A. ++ +++ 85 N.A. ++ +++ 86 N.A. ++ ++ 87 ++ +++ +++ 88 N.A. ++ +++ 89 N.A. ++ ++ 90 N.A. ++ +++ 91 N.A. ++ +++ 92 N.A. ++ + 93 N.A. ++ ++ 94 N.A. ++ +++ 95 N.A. ++ +++ 96 N.A. + + 97 + +++ ++++ 98 ++ +++ ++++ 99 +++ +++ ++++ 100 +++ +++ ++++ 101 + +++ +++ 102 N.A. ++ ++++ 107 N.A. ++ ++++ 322 N.A. ++ +++ Table 5. in vitro KRAS HiBiT degradation assays with HEK293-KRAS-G12D cells HiBiT- HiBiT- HiBiT- Degradation Degradation Degradation HEK293.7 HEK293.7 HEK293.7 Compound KRAS_G12D KRAS_G12D KRAS_G12D (KI) (KI) (KI) 24 hours 24 hours 24 hours DC50 nM Emax IP nM 1 N.A. + + 2 N.A. + + 3 N.A. ++ + 4 N.A. + + 5 N.A. + + 6 N.A. + + 7 N.A. + + 8 N.A. + + 9 N.A. + + 10 N.A. + + 11 N.A. + + 12 N.A. + + 13 N.A. ++ + 14 N.A. + + 15 N.A. + + 16 N.A. + + 17 N.A. + + 18 N.A. + + 19 N.A. + + 20 N.A. + ++++ 21 N.A. + + 22 N.A. + ++++ 23 N.A. ++ + 24 N.A. + + 25 N.A. + + 26 N.A. + ++++ 27 N.A. + + 28 N.A. + + 29 N.A. + ++++ 30 N.A. + + 31 N.A. + + 32 N.A. + + 33 N.A. + + 34 N.A. ++ + 35 N.A. + + 36 N.A. + + 37 N.A. + + 38 N.A. ++ + 39 N.A. + + 40 + +++ +++ 41 + +++ ++ 42 N.A. ++ + 43 N.A. ++ + 44 N.A. ++ +++ 45 N.A. ++ + 46 N.A. ++ + 47 N.A. ++ + 48 N.A. ++ + 49 N.A. + + 50 N.A. ++ + 51 N.A. + + 52 N.A. ++ + 53 N.A. + + 54 + +++ ++ 55 N.A. ++ + 56 N.A. ++ + 57 N.A. ++ + 58 N.A. + + 59 N.A. ++ +++ 60 N.A. + + 61 N.A. + + 62 N.A. + + 63 N.A. + + 64 +++ +++ +++ 65 + +++ +++ 66 N.A. ++ +++ 67 N.A. ++ +++ 68 N.A. ++ +++ 69 +++ +++ +++ 70 + +++ +++ 71 N.A. ++ +++ 72 N.A. ++ +++ 73 N.A. + + 74 N.A. ++ + 75 N.A. ++ +++ 76 N.A. ++ +++ 77 ++ +++ +++ 78 N.A. ++ + 79 N.A. + + 80 N.A. + + 81 N.A. + + 82 + +++ +++ 83 + +++ +++ 84 + +++ +++ 85 +++ +++ ++++ 86 + +++ +++ 87 + +++ +++ 88 + +++ +++ 89 + +++ + 90 ++ +++ ++++ 91 N.A. ++ ++ 92 N.A. ++ + 93 N.A. ++ ++ 94 N.A. ++ +++ 95 ++ +++ +++ 96 N.A. + + 97 + +++ +++ 98 ++ +++ +++ 99 +++ +++ +++ 100 +++ +++ ++++ 101 + +++ +++ 102 +++ +++ ++++ 107 +++ +++ ++++ 109 +++ +++ ++++ 131 +++ +++ ++++ 139 N.A. ++ ++++ 144 +++ +++ ++++ 148 +++ +++ ++++ 152 ++ +++ +++ 153 N.A. ++ +++ 154 +++ +++ ++++ 156 N.A. ++ +++ 157 N.A. ++ +++ 158 N.A. ++ +++ 159 N.A. ++ +++ 161 N.A. ++ + 162 +++ +++ ++++ 163 +++ +++ ++++ 164 +++ +++ ++++ 165 N.A. ++ ++++ 166 +++ +++ ++++ 169 +++ +++ +++ 170 +++ +++ ++++ 171 ++++ +++ ++++ 172 +++ +++ ++++ 208 N.A. ++ + 322 N.A. ++ +++ 324 +++ +++ +++ 329 N.A. ++ + Table 6. in vitro KRAS HiBiT degradation assays with HEK293-KRAS-G12 WT, cells HiBiT- HiBiT- HiBiT- Degradation Degradation Degradation HEK293.8 HEK293.8 HEK293.8 Compound KRAS_WT KRAS_WT KRAS_WT (KI) (KI) (KI) 24 hours 24 hours 24 hours DC50 nM Emax IP nM 1 N.A. ++ +++ 2 N.A. + + 3 N.A. ++ + 4 N.A. + + 5 N.A. + + 6 N.A. + + 7 N.A. ++ + 8 N.A. ++ ++ 9 N.A. ++ +++ 10 N.A. ++ + 11 N.A. ++ + 12 N.A. ++ + 13 N.A. ++ +++ 14 N.A. + + 15 N.A. + + 16 N.A. + + 17 N.A. + + 18 N.A. + + 19 N.A. + + 20 N.A. + + 21 N.A. + + 22 N.A. + + 23 N.A. ++ + 24 N.A. ++ + 25 N.A. ++ + 26 N.A. + + 27 N.A. + + 28 N.A. + + 29 N.A. ++ + 30 N.A. + + 31 N.A. + + 32 N.A. + +++ 33 N.A. + +++ 34 + +++ ++ 35 N.A. + + 36 N.A. ++ + 37 N.A. + + 38 N.A. + + 39 N.A. + + 40 +++ +++ +++ 41 ++ +++ +++ 42 + +++ + 43 ++ +++ +++ 44 ++ +++ +++ 45 + +++ + 46 + +++ ++ 47 + +++ ++ 48 N.A. ++ + 49 N.A. ++ + 50 N.A. ++ + 51 N.A. ++ ++ 52 N.A. ++ +++ 53 + +++ +++ 54 ++ +++ +++ 55 N.A. ++ + 56 N.A. ++ + 57 + +++ + 58 N.A. + + 59 ++ +++ +++ 60 N.A. ++ ++ 61 N.A. + + 62 N.A. ++ + 63 N.A. ++ + 64 +++ +++ +++ 65 +++ +++ +++ 66 ++ +++ +++ 67 + +++ +++ 68 + +++ +++ 69 +++ +++ +++ 70 +++ +++ +++ 71 + +++ +++ 72 N.A. ++ +++ 73 N.A. ++ ++ 74 N.A. ++ + 75 N.A. ++ +++ 76 +++ +++ +++ 77 +++ +++ +++ 78 N.A. ++ + 79 N.A. ++ + 80 N.A. ++ + 81 N.A. ++ + 82 +++ +++ +++ 83 +++ +++ +++ 84 +++ +++ +++ 85 ++++ +++ ++++ 86 +++ +++ +++ 87 +++ +++ +++ 88 +++ +++ +++ 89 + +++ ++ 90 ++++ +++ ++++ 91 + +++ +++ 92 + +++ + 93 ++ +++ +++ 94 +++ +++ +++ 95 +++ +++ +++ 96 N.A. ++ + 97 +++ +++ +++ 98 +++ +++ +++ 99 +++ +++ +++ 100 ++++ +++ ++++ 101 ++ +++ +++ 102 ++++ +++ ++++ 107 ++++ +++ ++++ 109 ++++ +++ ++++ 131 ++++ +++ ++++ 139 ++++ +++ ++++ 144 +++ +++ +++ 148 ++++ +++ ++++ 152 +++ +++ ++++ 153 N.A. ++ ++ 154 ++++ +++ ++++ 156 +++ +++ +++ 157 +++ +++ +++ 158 +++ +++ ++++ 159 +++ +++ ++++ 161 +++ +++ ++++ 162 ++++ +++ ++++ 163 ++++ +++ ++++ 164 +++ +++ ++++ 165 N.A. ++ + 166 ++++ +++ ++++ 169 N.A. ++ +++ 170 ++++ +++ ++++ 171 ++++ +++ ++++ 172 ++++ +++ ++++ 208 N.A. + + 322 +++ +++ +++ 324 ++++ +++ ++++ 329 + +++ + Example 6: HiBiT KRAS Degradation Assay Phenol red-free Dulbecco’s modified Eagle medium (DMEM), phenol-red free Leibovitz’s L-15 medium, fetal bovine serum (FBS), and 1 M HEPES were purchased from Thermo Fisher Scientific (Waltham, MA, USA). The Nano-Glo® HiBiT Lytic Assay System was purchased from Promega (Madison, WI, USA). Cell culture flasks and 384-well microplates were acquired from VWR (Radnor, PA, USA). The following ready-to-use HiBiT reporter cell lines were acquired from Promega (Madison, WI, USA): HEK293-KRAS-WT (Cat#CS3023186) exclusively expressing HiBiT-KRAS-WT wild-type protein (also referred to here as HEK293.8); HEK293-KRAS-G12D (Cat#CS3023372) exclusively expressing HiBiT- KRAS-G12D mutant protein (also referred to here as HEK293.7); and SW620-KRAS-G12V (Cat#3023152) exclusively expressing HiBiT-KRAS-G12V mutant protein (also referred to here as SW620.2). For each of these cell lines, the HiBiT fusion tag was genetically engineered into the N-terminus of endogenously expressed KRAS via CRISPR. HiBiT-KRAS degradation was evaluated by the quantification of luminescent signals using the Nano-Glo® HiBiT Lytic Assay kit. Test compounds were added to 384-well plates in duplicate using an 11-point half-log dilution series, with the highest dose set to 10 μΜ. The HEK293.8, HEK293.7, or SW620.2 cells in their respective growth medium were then added into the compound-containing 384-well plates. The HEK293-KRAS-WT and HEK293-KRAS- G12D cells were cultured in DMEM-based growth medium supplemented with 10% FBS and 10 mM HEPES; while SW620-KRAS-G12V cells were maintained in L-15 medium supplemented with 10% FBS and 10 mM HEPES. The cellular plating density per well in the 30 μL total assay volume for each cell line is as follows: 10,000 cells for HEK293-KRAS-WT and HEK293-KRAS-G12D cells; and 7,000 cells for SW620-KRAS-G12V cells. Upon cell addition, plates with HEK293.8 or HEK293.7 cells were incubated with compounds at 37 °C with 5% CO2 for 24 hours. As a CO2 and air mixture are detrimental to SW620-KRAS-G12V cells using L-15 medium, this cell line was incubated in a humidified 37 °C incubator without CO_2. Following the 24-hour incubation, Nano-Glo^® HiBiT Lytic Assay reagents were added to the cells per the manufacturer’s instructions. Luminescence was acquired using an EnVision™ Multilabel Reader (PerkinElmer, Santa Clara, CA, USA). Quantification of luminescence responses measured in the presence of compound were normalized to a high signal/no degradation control (untreated cells + lytic detection reagent) and a low signal/full degradation control (untreated cells, no lytic detection reagent). Data were analyzed with a 4-parameter logistic fit to generate sigmoidal dose-response curves. The DC50 is the concentration of compound at which exactly 50% of the total cellular KRAS has been degraded. The Emax, or maximum effect of each compound, represents the amount of residual protein remaining in the cell following compound treatment. The IP, or inflection point of the dose-response curve, is the concentration of compound at which 50% of the observed degradation response is achieved. Tables 7-9 show the activity of selected compounds of this invention in the in vitro KRAS HiBiT degradation assays with SW620-KRAS-G12V, HEK293-KRAS-G12D, and HEK293-KRAS-WT cells, respectively, wherein each compound number corresponds to the compound numbering set forth in Synthesis 1-191 described herein. The experiment was conducted at least once for each compound identified in Tables 7-9, where if the experiment was conducted multiple times, then the data shown in the table is the average of the two or more experiments. “++++” represents a DC₅₀ or IP value of less than 100 nM or an Emax of less than 10%. “+++” represents a DC50 or IP value of 100 nM–500 nM or an Emax value of 10%–50%. “++” represents a DC₅₀ or IP value of 500 nM–1000 nM or an Emax value of 50%–90%. “+” represents a DC50 or IP value of greater than 1000 nM or an Emax value of more than 90%. N.A. means Emax is greater than or equal to 50%. Table 7. in vitro KRAS HiBiT degradation assays with SW620-KRAS-G12V cells HiBiT- HiBiT- HiBiT- Degradation Degradation Degradation SW620.2 SW620.2 SW620.2 Compound KRAS_G12V KRAS_G12V KRAS_G12V (KI) (KI) (KI) 24 hours 24 hours 24 hours DC50 nM Emax IP nM 34 N.A. ++ +++ 40 N.A. ++ ++++ 41 N.A. ++ +++ 77 +++ +++ ++++ 97 ++ +++ ++++ 98 +++ +++ ++++ 99 ++ +++ +++ 100 ++++ +++ ++++ 102 +++ +++ ++++ 103 N.A. ++ ++++ 104 + +++ +++ 105 +++ +++ +++ 106 N.A. ++ ++++ 107 N.A. ++ ++++ 108 N.A. ++ ++++ 109 N.A. ++ ++++ 110 N.A. + + 111 N.A. ++ ++++ 112 N.A. ++ ++ 113 N.A. ++ ++++ 114 N.A. ++ ++++ 115 ++++ +++ ++++ 116 N.A. ++ +++ 117 N.A. ++ ++++ 118 N.A. ++ ++++ 119 N.A. ++ ++++ 120 N.A. ++ ++++ 121 N.A. ++ ++++ 122 N.A. ++ +++ 123 N.A. ++ +++ 124 N.A. ++ ++++ 125 N.A. ++ ++++ 126 N.A. ++ ++++ 127 N.A. + + 128 ++++ +++ ++++ 131 +++ +++ ++++ 132 N.A. ++ +++ 133 N.A. ++ ++++ 134 N.A. ++ ++++ 135 +++ +++ ++++ 136 N.A. ++ ++++ 137 +++ +++ ++++ 138 N.A. ++ +++ 139 N.A. ++ ++++ 140 N.A. ++ ++++ 141 +++ +++ ++++ 142 N.A. ++ ++++ 143 N.A. ++ ++++ 144 N.A. ++ ++++ 145 +++ +++ ++++ 146 N.A. + + 147 N.A. + + 148 +++ +++ ++++ 149 +++ +++ ++++ 152 N.A. ++ ++++ 153 N.A. ++ +++ 154 N.A. ++ ++++ 155 N.A. ++ ++++ 156 N.A. ++ ++++ 157 N.A. ++ +++ 158 N.A. ++ ++++ 159 +++ +++ +++ 160 N.A. + + 161 N.A. + + 162 ++++ +++ + 163 +++ +++ ++++ 164 N.A. ++ ++++ 165 N.A. + + 166 N.A. ++ ++++ 169 N.A. ++ +++ 170 N.A. ++ ++++ 171 N.A. ++ ++++ 172 ++++ +++ ++++ 181 N.A. ++ +++ 182 N.A. ++ ++++ 183 N.A. ++ ++++ 184 N.A. + + 203 N.A. ++ ++++ 204 N.A. ++ +++ 206 N.A. + + 208 N.A. + + 209 N.A. + + 281 +++ +++ ++++ 296 ++++ +++ ++++ 299 N.A. ++ ++++ 324 +++ +++ ++++ 326 +++ +++ ++++ 327 +++ +++ ++++ 328 N.A. + + 329 N.A. ++ ++ Table 8. in vitro KRAS HiBiT degradation assays with HEK293-KRAS-G12D cells HiBiT- HiBiT- HiBiT- Degradation Degradation Degradation HEK293.7 HEK293.7 HEK293.7 Compound KRAS_G12D KRAS_G12D KRAS_G12D (KI) (KI) (KI) 24 hours 24 hours 24 hours DC50 nM Emax IP nM 34 N.A. ++ + 41 + +++ +++ 97 + +++ ++++ 98 + +++ +++ 99 +++ +++ ++++ 100 +++ +++ ++++ 102 +++ +++ ++++ 103 ++ +++ ++++ 104 + +++ +++ 105 ++ +++ +++ 106 N.A. ++ +++ 107 +++ +++ ++++ 108 ++ +++ +++ 110 N.A. + + 111 +++ +++ ++++ 112 N.A. + ++ 113 N.A. ++ +++ 114 N.A. ++ ++++ 115 +++ +++ ++++ 116 N.A. ++ +++ 117 N.A. ++ +++ 118 N.A. ++ +++ 119 +++ +++ ++++ 120 +++ +++ ++++ 121 +++ +++ ++++ 122 ++ +++ +++ 123 + +++ +++ 124 N.A. ++ +++ 125 ++ +++ +++ 126 N.A. ++ +++ 127 N.A. + + 128 ++++ +++ ++++ 131 ++ +++ ++++ 132 N.A. ++ +++ 133 N.A. ++ +++ 134 N.A. ++ ++++ 135 N.A. ++ +++ 136 N.A. ++ +++ 137 +++ +++ ++++ 138 N.A. ++ +++ 139 N.A. ++ ++++ 140 N.A. ++ ++++ 141 +++ +++ ++++ 142 N.A. ++ +++ 143 + +++ +++ 145 +++ +++ ++++ 146 N.A. + + 147 N.A. ++ + 149 +++ +++ ++++ 181 + +++ +++ 182 ++ +++ +++ 183 +++ +++ +++ 184 + +++ ++ 203 + ++ +++ 204 N.A. ++ + 206 N.A. ++ + 209 N.A. + + Table 9. in vitro KRAS HiBiT degradation assays with HEK293-KRAS-G12 WT, cells HiBiT- HiBiT- HiBiT- Degradation Degradation Degradation HEK293.8 HEK293.8 HEK293.8 Compound KRAS_WT KRAS_WT KRAS_WT (KI) (KI) (KI) 24 hours 24 hours 24 hours DC50 nM Emax IP nM 34 N.A. ++ ++ 40 +++ +++ +++ 41 +++ +++ +++ 77 +++ +++ +++ 97 +++ +++ ++++ 98 ++ +++ ++++ 99 + +++ +++ 100 ++++ +++ ++++ 102 ++++ +++ ++++ 103 ++++ +++ ++++ 104 ++ +++ +++ 105 +++ +++ ++++ 106 N.A. ++ ++ 107 ++++ +++ ++++ 108 ++++ +++ ++++ 110 N.A. + + 111 +++ +++ ++++ 112 N.A. + + 113 ++++ +++ ++++ 114 ++++ +++ ++++ 115 ++++ +++ ++++ 116 N.A. ++ ++++ 117 ++++ +++ ++++ 118 ++++ +++ ++++ 119 ++++ +++ ++++ 120 ++++ +++ ++++ 121 ++++ +++ ++++ 122 +++ +++ ++++ 123 +++ +++ ++++ 124 +++ +++ ++++ 125 +++ +++ +++ 126 N.A. ++ +++ 127 N.A. + + 128 ++++ +++ ++++ 131 ++++ +++ ++++ 132 N.A. ++ +++ 133 N.A. ++ ++++ 134 + +++ +++ 135 ++++ +++ ++++ 136 +++ +++ ++++ 137 ++++ +++ ++++ 138 +++ +++ +++ 139 +++ +++ ++++ 140 N.A. ++ ++++ 141 ++++ +++ ++++ 142 N.A. ++ ++++ 143 ++++ +++ ++++ 145 ++++ +++ ++++ 146 N.A. + + 147 N.A. + + 149 ++++ +++ ++++ 181 ++ +++ +++ 182 +++ +++ +++ 183 ++++ +++ ++++ 184 N.A. ++ + 203 + +++ +++ 204 N.A. ++ ++ 206 N.A. ++ + 209 N.A. + + Example 7: HiBiT KRAS Degradation Assay Phenol red-free Dulbecco’s modified Eagle medium (DMEM), phenol-red free Leibovitz’s L-15 medium, fetal bovine serum (FBS), and 1 M HEPES were purchased from Thermo Fisher Scientific (Waltham, MA, USA). The Nano-Glo® HiBiT Lytic Assay System was purchased from Promega (Madison WI USA) Cell culture flasks and 384-well microplates were acquired from VWR (Radnor, PA, USA). The following ready-to-use HiBiT reporter cell lines were acquired from Promega (Madison, WI, USA): HEK293-KRAS-WT (Cat#CS3023186) exclusively expressing HiBiT-KRAS-WT wild-type protein (also referred to here as HEK293.8); and HEK293-KRAS-G12D (Cat#CS3023372) exclusively expressing HiBiT-KRAS-G12D mutant protein (also referred to here as HEK293.7). For each of these cell lines, the HiBiT fusion tag was genetically engineered into the N-terminus of endogenously expressed KRAS via CRISPR. HiBiT-KRAS degradation was evaluated by the quantification of luminescent signals using the Nano-Glo® HiBiT Lytic Assay kit. Test compounds were added to 384-well plates in duplicate using an 11-point half-log dilution series, with the highest dose set to 10 μΜ. The HEK293.8 or HEK293.7 cells in their respective growth medium were then added into the compound-containing 384-well plates. The HEK293-KRAS-WT and HEK293-KRAS-G12D cells were cultured in DMEM-based growth medium supplemented with 10% FBS and 10 mM HEPES. The cellular plating density per well in the 30 μL total assay volume 10,000 cells for both the HEK293-KRAS-WT and HEK293-KRAS-G12D cells. Upon cell addition, plates with HEK293.8 or HEK293.7 cells were incubated with compounds at 37 °C with 5% CO2 for 24 hours. Following the 24-hour incubation, Nano-Glo^® HiBiT Lytic Assay reagents were added to the cells per the manufacturer’s instructions. Luminescence was acquired using an EnVision™ Multilabel Reader (PerkinElmer, Santa Clara, CA, USA). Quantification of luminescence responses measured in the presence of compound were normalized to a high signal/no degradation control (untreated cells + lytic detection reagent) and a low signal/full degradation control (untreated cells, no lytic detection reagent). Data were analyzed with a 4-parameter logistic fit to generate sigmoidal dose-response curves. The DC50 is the concentration of compound at which exactly 50% of the total cellular KRAS has been degraded. The Emax, or maximum effect of each compound, represents the amount of residual protein remaining in the cell following compound treatment. The IP, or inflection point of the dose-response curve, is the concentration of compound at which 50% of the observed degradation response is achieved. Tables 10 and 11 show the activity of selected compounds of this invention in the in vitro KRAS HiBiT degradation assays with HEK293-KRAS-G12D and HEK293-KRAS-WT cells, respectively, wherein each compound number corresponds to the compound numbering set forth in Synthesis 1-191 described herein. The experiment was conducted at least once for each compound identified in Tables 10-11, where if the experiment was conducted multiple times, then the dat h i h bl i h f h e experiments. “++++” represents a DC₅₀ or IP value of less than 100 nM or an Emax of less than 10%. “+++” represents a DC₅₀ or IP value of 100 nM–500 nM or an Emax value of 10%–50%. “++” represents a DC50 or IP value of 500 nM–1000 nM or an Emax value of 50%–90%. “+” represents a DC₅₀ or IP value of greater than 1000 nM or an Emax value of more than 90%. N.A. means Emax is greater than or equal to 50%. Table 10. in vitro KRAS HiBiT degradation assays with HEK293-KRAS-G12D cells Compound HiBiT- HiBiT- HiBiT- Degradation Degradation Degradation HEK293.7 HEK293.7 HEK293.7 KRAS_G12D KRAS_G12D KRAS_G12D (KI) (KI) (KI) 24 hours 24 hours 24 hours DC50 nM Emax IP nM 10 N.A. ++ + 34 N.A. + + 40 +++ +++ +++ 43 N.A. ++ + 64 +++ +++ ++++ 77 N.A. ++ ++++ 100 +++ +++ ++++ 107 +++ +++ ++++ 109 ++ +++ ++++ 128 ++++ +++ ++++ 144 ++ +++ ++++ 148 ++++ +++ ++++ 152 N.A. ++ +++ 153 N.A. + + 154 + +++ ++++ 155 N.A. ++ + 156 N.A. ++ +++ 157 N.A. ++ +++ 158 + +++ +++ 159 ++ +++ +++ 160 N.A. + + 161 N.A. ++ + 162 ++++ +++ ++++ 163 +++ +++ ++++ 164 N.A. ++ ++++ 165 N.A. ++ + 166 +++ +++ ++++ 169 N.A. ++ ++++ 170 ++++ +++ ++++ 171 ++++ +++ ++++ 172 ++++ +++ ++++ 208 N.A. ++ + 281 ++++ +++ ++++ 296 ++++ +++ ++++ 298 N.A. ++ + 299 + +++ +++ 324 N.A. ++ ++++ 326 ++++ +++ ++++ 327 N.A. ++ ++++ 328 N.A. + + 329 N.A. ++ ++ Table 11. in vitro KRAS HiBiT degradation assays with HEK293-KRAS-G12 WT, cells Compound HiBiT- HiBiT- HiBiT- Degradation Degradation Degradation HEK293.8 HEK293.8 HEK293.8 KRAS_WT KRAS_WT KRAS_WT (KI) (KI) (KI) 24 hours 24 hours 24 hours DC50 nM Emax IP nM 10 N.A. ++ +++ 34 N.A. ++ + 40 +++ +++ ++++ 43 N.A. ++ +++ 64 ++++ +++ ++++ 77 +++ +++ ++++ 100 ++++ +++ ++++ 107 ++++ +++ ++++ 109 ++++ +++ ++++ 128 ++++ +++ ++++ 144 + +++ ++++ 148 ++++ +++ ++++ 152 +++ +++ +++ 153 N.A. + +++ 154 ++++ +++ ++++ 155 N.A. ++ ++ 156 +++ +++ +++ 157 +++ +++ ++++ 158 +++ +++ ++++ 159 +++ +++ ++++ 160 N.A. ++ + 161 +++ +++ ++++ 162 ++++ +++ ++++ 163 ++++ +++ ++++ 164 +++ +++ ++++ 165 N.A. ++ ++++ 166 ++++ +++ ++++ 169 N.A. ++ + 170 ++++ +++ ++++ 171 ++++ +++ ++++ 172 +++ +++ ++++ 208 N.A. ++ + 281 ++++ +++ ++++ 296 ++++ +++ ++++ 298 N.A. ++ + 299 +++ +++ ++++ 324 ++++ +++ ++++ 326 ++++ +++ ++++ 327 +++ +++ ++++ 328 N.A. ++ + 329 N.A. ++ + All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teaching of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the invention as defined in the appended claims. Additionally, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the present application.

Claims

CLAIMS We claim 1. A compound of Formula: or a pharmaceutically acceptable salt thereof; wherein: KRAS Targeting Ligand^B is ; Heterocyclic Moiety^A is selected from: , and ; Q is CH₂, NR², , O, or S; R¹ and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R¹ and R⁶ are combined to form a one or two carbon bridge to form a fused cycle; each R² is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R⁹, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)₂R⁹, -SC(O)R⁹, -OS(O)₂R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, -NR⁷P(O)(R⁹)₂, and -OP(O)(R⁹)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R¹⁶ is selected from: , , , , and , and R¹², each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R¹⁷ is selected from: , , , , and , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R¹⁸ is a 9-membered heteroaryl attached to the azaglutarimide moiety through a C-N bond, optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; R¹² is the attachment point to Linker; R⁷ and R⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR⁷R⁸, -OR⁷, and -SR⁷ each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(O)(R¹⁴)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; R¹¹ and R¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(O)(R¹⁴)₂; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2 each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂; R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; R³⁰ and R³¹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R³³ is selected from: , , and each of which R³³ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; and each R⁴⁵, R⁴⁶, and R⁴⁷ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(O)(R¹⁴)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; Linker is selected from ; wherein: X¹ and X² are independently at each occurrence selected from bond, heterocycle, NR², C(R²)₂, O, C(O), and S; R²⁰, R²¹, R²², R²³, and R²⁴ are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO₂-, -S(O)-, -C(S)-, -C(O)NR²-, -NR²C(O)-, -O-, -S-, -NR²-, -C(R⁴⁰R⁴⁰)-, -P(O)(OR²⁶)O-, -P(O)(OR²⁶)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁰; R²⁶ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle; and R⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl)₂, -NHSO₂(alkyl), -N(alkyl)SO₂alkyl, -NHSO₂(aryl, heteroaryl or heterocycle), -N(alkyl)SO₂(aryl, heteroaryl or heterocycle), -NHSO₂alkenyl, -N(alkyl)SO₂alkenyl, -NHSO₂alkynyl, -N(alkyl)SO₂alkynyl, haloalkyl, aryl, heteroaryl, heterocycle, and cycloalkyl. 2. A compound of Formula: ; or a pharmaceutically acceptable salt thereof;

wherein: Heterocyclic Moiety^B is selected from: , and ; Q is CH₂, NR², , O, or S; Q² is CH2, , O, or S; R¹ and R⁶ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R¹ and R⁶ are combined to form a one or two carbon bridge to form a fused cycle; each R² and R⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R⁹, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR⁷R⁸, -OR⁷, -SR⁷, -C(O)R⁹, -C(S)R⁹, -S(O)R⁹, -S(O)₂R⁹, -OC(O)R⁹, -OC(S)R⁹, -OS(O)R⁹, -OS(O)₂R⁹, -SC(O)R⁹, -OS(O)₂R⁹, -NR⁷C(O)R⁹, -NR⁷C(S)R⁹, -NR⁷S(O)R⁹, -NR⁷S(O)₂R⁹, -P(O)(R⁹)₂, -SP(O)(R⁹)₂, - NR⁷P(O)(R⁹)₂, and -OP(O)(R⁹)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R¹⁶ is selected from: , , , , and , and R¹², each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R^16B is selected from: , , , and ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; R^17B is selected from: and ; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵; Cycle-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-A is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8- membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein Cycle-B is optionally substituted with 1 or 2 substituents independently selected from R⁵; Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; Cycle² is a fused heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵ and substituted with one R¹² substituent; R¹² is the attachment point to Linker; R⁷ and R⁸ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R¹⁴ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R⁹ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR⁷R⁸, -OR⁷, and -SR⁷ each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; each R¹⁰ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(O)(R¹⁴)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; R¹¹ and R¹³ at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(O)(R¹⁴)₂; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁴ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂ each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; each R¹⁵ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)₂; KRAS Targeting Ligand^A is selected from: , , , , , , , , and ; R²⁹ is selected from aryl, heteroaryl, and bicycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁴⁵, R⁴⁶, and R⁴⁷; R³⁰ and R³¹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R³² is selected from: and ; wherein attachment point is attached to the Linker and the remaining attachment point is attached to the KRAS Targeting Moiety; R⁵¹ and R^51A are independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, -NR⁷R⁸, -OR⁷, and -SR⁷; R⁸⁸ is selected at each instance from aryl, heteroaryl, heterocycle, bicycle, and spirocycle; z is independently selected at each instance from 0, 1, 2, 3, or 4 as allowed by valence; q is 1, 2, 3, or 4; w is 1, 2, 3, or 4; X^A is selected from -CH- and -N-; X^B is selected from -CH₂-, -C(R⁵¹)₂-, -O-, -NH-, -N(R⁴)-, and -S-; R³³ is selected from: , , and each of which R³³ is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, halogen haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, bicycle, -NR⁷R⁸, -OR⁷, and -SR⁷; X is selected from -O-, -NH-, -N(alkyl)-, and -S-; R³⁸ and R³⁹ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, and heterocycle each of which except hydrogen and halogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰; R⁴¹, R⁴², R⁴³, and R⁴⁴ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, and halogen; and each R⁴⁵, R⁴⁶, and R⁴⁷ is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR¹¹R¹³, -OR¹¹, -SR¹¹, -C(O)R¹⁴, -C(S)R¹⁴, -S(O)R¹⁴, -S(O)₂R¹⁴, and -P(O)(R¹⁴)₂; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵; Linker is selected from ; X¹ and X² are independently at each occurrence selected from bond, heterocycle, NR², C(R²)₂, O, C(O), and S; R²⁰, R²¹, R²², R²³, and R²⁴ are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO₂-, -S(O)-, -C(S)-, -C(O)NR²-, -NR²C(O)-, -O-, -S-, -NR²-, -C(R⁴⁰R⁴⁰)-, -P(O)(OR²⁶)O-, -P(O)(OR²⁶)-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1,

2, 3, or 4 substituents independently selected from R⁴⁰; R²⁶ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle; and R⁴⁰ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl)₂, -NHSO₂(alkyl), -N(alkyl)SO₂alkyl, -NHSO₂(aryl, heteroaryl or heterocycle), -N(alkyl)SO₂(aryl, heteroaryl or heterocycle), -NHSO₂alkenyl, -N(alkyl)SO₂alkenyl, -NHSO₂alkynyl, -N(alkyl)SO₂alkynyl, haloalkyl, aryl, heteroaryl, heterocycle, and cycloalkyl.

3. The compound of claim 2, wherein Heterocyclic Moiety^B is selected from , , and .

4. The compound of claim 1, wherein Heterocyclic Moiety^A is .

5. The compound of claim 4, wherein Q is NH, NCH₃, O, or S.

6. The compound of claim 1, wherein Heterocyclic Moiety^A is .

7. The compound of any one of claims 1-6, wherein R¹ is hydrogen.

8. The compound of any one of claims 1 and 4-7, wherein R¹⁶ and R¹⁷ are selected from , , , , , and .

9. The compound of any one of claims 1-2 and 4-7, wherein R¹⁶, R^16B and R¹⁷ are selected from , , , , , , , , , , ,

. , , , , , and .

10. The compound of claim 1, wherein Heterocyclic Moiety^A is .

11. The compound of claim 10, wherein R¹⁸ is , , , , , , , , , , , , , , , , , or .

12. The compound of claim 1 or claim 2, wherein Heterocyclic Moiety^A and Heterocyclic Moiety^B are or 13. The compound of any one of claims 1-12, wherein R⁶ is hydrogen. 14. The compound of any one of claims 1-13, wherein each R⁵ is independently selected from hydrogen, alkyl, haloalkyl, and halogen. 15. The compound of any one of claims 1-14, wherein Linker is of formula: . 16. The compound of any one of claims 1-15, wherein X¹ is bond, heterocycle, or -NR²-. 17. The compound of any one of claims 1-16, wherein R²³ is bond, heterocycle, or -NR²-. 18. The compound of any one of claims 1-17, wherein R²⁰ is alkyl, heterocycle, aryl, -heteroaryl or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R⁴⁰. 19. The compound of any one of claims 1-18, wherein R²¹ is bond, -O-, -NR²-, -S-, alkyl, heterocycle, aryl, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R⁴⁰. 20. The compound of any one of claims 1-19, wherein R²² is alkyl, heterocycle, aryl, heteroaryl, or bicycle, each of which is optionally substituted with 1 or 2 substituents independently selected from R⁴⁰. 21. The compound of any one of claims 2-20, wherein the KRAS Targeting Ligand^A is . 22. The compound of any one of claims 2-21, wherein R³² is selected from , , , , and ; wherein: R^51B is independently selected from halogen, cyano, haloalkyl, -OR⁷, and -SR⁷; R^51C is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cyano and CD₃; and R^51D and R^51E are independently hydrogen, alkyl, alkenyl, haloalkyl, cyano, -OR⁷, and -SR⁷ or together with X^B and the carbon atoms to which they are attached, form a 5-, 6-, or 7- membered ring. 23. The compound of any one of claims 1-22, wherein R²⁹ is . 24. The compound of any one of claims 1-23, wherein R³³ is , , , ,

, , , , R⁵² R⁵³ X OR⁵⁷ N R⁵⁴ _R ⁵⁵ , or ; wherein R⁵² and R⁵⁴ are independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; R⁵³ and R⁵⁵ are independently selected at each instance from hydrogen, halogen, alkyl, haloalkyl, -NR⁷R⁸, -OR⁷, -SR⁷, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and bicycle; and R⁵⁷ is independently selected from hydrogen, alkyl, haloalkyl, arylalkyl, C(O)R⁴, C(O)NR⁷R⁸, and R⁷. 25. The compound of claim 1 or claim 2, wherein the compound is selected from the compounds of Table 3B or a pharmaceutically acceptable salt thereof. 26. A compound of Table 3A or a pharmaceutically acceptable salt thereof. 27. A pharmaceutical composition comprising a compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 28. The pharmaceutical composition of claim 27 for the treatment of a KRAS mediated cancer. 29. A method of treating a KRAS mediated cancer comprising administering an effective amount of a compound of any one of claims 1-26 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to a human patient in need thereof. 30. Use of a compound of any one of claims 1-26 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the treatment of a KRAS mediated cancer. 31. Use of a compound of any one of claims 1-26 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament to treat a KRAS mediated cancer.